Dana-Farber Cancer Institute

CANCER CENTER SUPPORT GRANT

ECOG-ACRIN NETWORK GROUP STATISTICS AND DATA MANAGEMENT CENTER

DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES IN HUMAN LEUKEMIAS

SPORE IN MYELOMA

DF/HCC SPORE IN GASTROINTESTINAL CANCER

HUMAN TUMOR ATLAS NETWORK: DATA COORDINATING CENTER

GENOMIC ANALYSIS OF NETWORK PERTURBATIONS IN HUMAN DISEASE

INTEGRATIVE ONCOGENOMICS OF MULTIPLE MYELOMA

SPORE: DANA-FARBER/HARVARD CANCER CENTER SPORE IN BREAST CANCER

U MASS BOSTON / DFHCC U54 PARTNERSHIP (1 OF 2)

DANA-FARBER/HARVARD CANCER CENTER ET-CTN WITH PHASE I EMPHASIS

DF/HCC SPORE IN PROSTATE CANCER

CANCER IMMUNE MONITORING AND ANALYSIS CENTER

PROTEIN KINASE THERAPEUTIC TARGETS FOR NON-SMALL CELL LUNG CARCINOMA

MECHANISMS OF GVHD

ANTIGEN PRESENTATION IN HUMAN AUTOIMMUNE DISEASES

COMPREHENSIVE DISSECTION OF THE CLL GENOME AND PHENOME TO IMPROVE PATIENT OUTCOMES

PAPOVA VIRUS TRANSFORMING MECHANISMS

BIOLOGY AND STRUCTURE OF PMHC RECEPTORS FUNCTIONING AS MECHANOSENSORS IN THE [ALPHA][BETA] T-CELL LINEAGE

IMMUNE MODULATION AFTER ALLOGENEIC HCT

ECOG STATISTICAL OFFICE

HOST-TUMOR CELL INTERACTIONS IN MYELOMA:

THE CELLULAR GEOGRAPHY OF THERAPEUTIC RESISTANCE IN CANCER

THE CENTER FOR THERAPEUTIC TARGETING OF EWS-ONCOPROTEINS

CHEMICAL BIOLOGY OF DIABETES

CANCORS STATISTICAL COORDINATING CENTER

HOW DO GENOME ALTERATIONS CAUSE HUMAN LUNG CANCER

TARGETING INTRATUMOR HETEROGENEITY IN BREAST CANCER

MOLECULAR PATHWAYS TO THYMIC LYMPHOMA AND LEUKEMIA

DISSECTING AND TARGETING DEREGULATED MITOCHONDRIAL APOPTOSIS IN HUMAN CANCER

DANA-FARBER/HARVARD CANCER CENTER SPORE IN LUNG CANCER

DANA FARBER/HARVARD CANCER CENTER OVARIAN CANCER SPORE GRANT

EVOLUTION AND TREATMENT RESPONSE OF BRAIN, BREAST, AND HEMATOLOGIC MALIGNANCIES

EVOLUTIONARY DYNAMICS OF BRAIN LUNG AND HEMATOPOIETIC TUMORS

GRADUATE TRAINING IN CANCER RESEARCH

PROGRAM PROJECT GRANT: MOLECULAR TARGETS OF GERMINAL CENTER B-CELL LYMPHOMAS

SPORE IN MYELOID MALIGNANCIES

MECHANISMS AND THERAPY OF CHRONIC GRAFT-VS.-HOST DISEASE - SUMMARY CHRONIC GVHD (CGVHD) IS THE MAJOR CAUSE OF LATE MORBIDITY, MORTALITY AND COMPROMISED ORGAN FUNCTION AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HCT). IT CAN AFFECT ESSENTIALLY ALL ORGANS AND TISSUES, INCLUDING THE LUNGS, WHERE THE DISEASE IS TERMED BRONCHIOLITIS OBLITERANS SYNDROME (BOS). BOS IS A PROGRESSIVE, IRREVERSIBLE, AND OFTEN FATAL LUNG DISEASE THAT OCCURS FOLLOWING HCT. BOS OCCURS IN APPROXIMATELY 5-10% OF HCT SURVIVORS AND IS CONSIDERED THE PULMONARY MANIFESTATION OF CGVHD. APPROXIMATELY 10-15% OF CGVHD PATIENTS WILL DEVELOP BOS, AND LESS THAN 15% OF BOS PATIENTS SURVIVE 5 YEARS. THE PRIMARY SITE OF INFLAMMATION IN BOS IS THE SMALL AIRWAY, EVENTUALLY LEADING TO FIBROSIS. CGVHD RESULTS FROM A FAILURE TO ACHIEVE IMMUNE TOLERANCE AFTER TRANSPLANT. THE MECHANISMS RESPONSIBLE FOR THE FAILURE OF TOLERANCE ARE COMPLEX AND INVOLVE MULTIPLE CELL TYPES, BUT T CELLS ARE CENTRAL TO THIS PROCESS. RESTING T CELLS PREFERENTIALLY USE MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION AS BASAL ENERGY. IN ACUTE GVHD, DONOR T CELLS EXPOSED TO HOST ALLOANTIGEN IN AN INFLAMMATORY ENVIRONMENT RAPIDLY DIFFERENTIATE AND PROLIFERATE, WITH BIOENERGETIC AND BIOSYNTHETIC NEEDS FULFILLED BY REPROGRAMMING METABOLISM AND USING MULTIPLE ENERGY SOURCES. IN CGVHD, METABOLISM DEMANDS ARE LESS WELL UNDERSTOOD, BUT WITH THE HIGH ENERGY DEMANDS OF PROLIFERATING IMMUNE CELLS IN CGVHD, STRATEGIES TO SPECIFICALLY BLOCK CRITICAL METABOLIC PATHWAYS MAY PROVE TO BE A NOVEL TREATMENT STRATEGY. IN THIS PROGRAM, WE FOCUS ON THE CRITICAL QUESTIONS THAT PLAGUE THE FIELD OF CGVHD. WE ADDRESS SHORTCOMINGS IN OUR UNDERSTANDING OF THE PATHOGENESIS OF HUMAN CGVHD AND OUR ABILITY TO PRIORITIZE THE NEXT GENERATION OF THERAPEUTIC STRATEGIES BY DEFINING THE IMMUNE NETWORKS THAT CHARACTERIZE PATIENTS WHO DEVELOP CGVHD AND INTERROGATE THE MECHANISMS OF BOTH SUCCESS AND FAILURE OF CGVHD TREATMENT REGIMENS. WE EXPLORE THE UNIQUE METABOLIC DEMANDS IN CGVHD PATHOGENESIS AND LUNG INJURY REPAIR AND FOCUS THERAPEUTICS ON THE MOST SEVERE MANIFESTATION OF CGVHD, BOS. WE EMPLOY NOVEL ORGANOID CULTURES AND IMMUNOGENOMICS TO PINPOINT THE CELLULAR AND ANTIGENIC TARGETS OF BOS. WE HAVE ASSEMBLED A COLLABORATIVE, MULTIDISCIPLINARY TEAM, UNIQUELY POISED TO MAKE SIGNIFICANT IMPACT IN THE FIELD.

THERAPEUTIC INDEX OF ACUTE LYMPHOBLASTIC LEUKEMIA

ELICITING B CELLS TO PRODUCE ANTI-HIV GP41 MPER-SPECIFIC NEUTRALIZING ANTIBODIES

DEVELOPING NOVEL TARGETED THERAPEUTICS INTEGRATED WITH IMMUNOTHERAPY-BASED APPROACHES TO MAKE BREAKTHROUGHS IN METASTATIC BREAST CANCER

A CONTROLLED CLINICAL TRIAL OF REGADENOSON IN SICKLE CELL ANEMIA

NEW PARADIGMS FOR TARGETING TRUNCAL DRIVER MUTATIONS

BIOCHEMICAL MECHANISM OF HIV DNA INTEGRATION

RAPID BROAD-SPECTRUM ANTI-MICROBIAL IMMUNITY BY PHAGE-ANTIBODY DELIVERY AND SELECTIVE VH GERMLINE STIMULATION

PERSONAL TUMOR NEOANTIGENS FOR IMMUNITY AGAINST CHRONIC LYMPHOCYTIC LEUKEMIA

HIV-1 PREINTEGRATION TRAFFICKING AND NUCLEAR LOCALIZATION

TARGETING IMMUNOGENICITY TO THE MPER HINGE AND C-HELIX FOR BNAB ELICITATION

PHOSPHOINOSITIDES AND CANCER METABOLISM

GENETICS OF PROSTATE CANCER IN AFRICA

DANA FARBER/HARVARD CANCER CENTER SPORE IN LUNG CANCER - PROJECT SUMMARY THIS APPLICATION IS A RESUBMISSION OF A SPECIALIZED PROGRAM OF RESEARCH EXCELLENCE (SPORE) IN LUNG CANCER ORIGINATING FROM THE LUNG CANCER PROGRAM OF THE DANA-FARBER/HARVARD CANCER CENTER (DF/HCC). THE DF/HCC SPORE IN LUNG CANCER INCLUDES RESEARCHERS FROM MULTIPLE HARVARD-AFFILIATED HOSPITALS INCLUDING THE DANA- FARBER CANCER INSTITUTE (DFCI), MASSACHUSETTS GENERAL HOSPITAL (MGH), BETH ISRAEL DEACONESS MEDICAL CENTER (BIDMC), BRIGHAM AND WOMEN’S HOSPITAL (BWH), AND BOSTON CHILDREN’S HOSPITAL (BCH), AS WELL AS HARVARD MEDICAL SCHOOL (HMS) AND HARVARD T.H. CHAN SCHOOL OF PUBLIC HEALTH (HSPH). PREVIOUSLY, THE DF/HCC LUNG CANCER PROGRAM WAS FUNDED BY A LUNG CANCER SPORE IN 2002. THIS WAS FOLLOWED BY A SUCCESSFUL RENEWAL APPLICATION IN 2007 AND A NO-COST EXTENSION FROM 2013-2015. THAT PERIOD OF TIME WAS ACCOMPANIED BY REMARKABLE PRODUCTIVITY BY OUR INVESTIGATORS, INCLUDING THE INITIAL DESCRIPTION OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS BY INVESTIGATORS AT BOTH MGH AND DFCI, IDENTIFICATION AND DEVELOPMENT OF 3RD GENERATION EGFR TYROSINE KINASE INHIBITORS (TKIS) WHICH ARE NOW IN WIDESPREAD CLINICAL USE, AND RAPID TRANSLATION OF EFFECTIVE ALK/ROS TARGETED THERAPIES, AMONG OTHER ACCOMPLISHMENTS. HOWEVER, DESPITE THE IMMENSE POSITIVE IMPACT OF TARGETED THERAPIES, THEY HAVE FAILED TO CURE ADVANCED LUNG ADENOCARCINOMA. OVER THE PAST 6 YEARS SINCE OUR PRIOR SPORE ENDED, THE DF/HCC LUNG PROGRAM HAS EVOLVED AND GROWN EVER MORE COLLABORATIVE. WE HAVE MAINTAINED A DEVELOPMENTAL RESEARCH PROGRAM TO SUPPORT A NEW CADRE OF INVESTIGATORS, WHO HAVE BUILT STRONG ADDITIONAL ARENAS OF EXPERTISE THAT ADD TO OUR LONGSTANDING TRADITION OF TARGETED THERAPY RESEARCH IN LUNG CANCER, INCLUDING INNATE AND ADAPTIVE IMMUNITY, SCLC BIOLOGY, CIRCULATING TUMOR DNA, AND LUNG CANCER SCREENING. THE DF/HCC LUNG CANCER PROGRAM THUS SEEKS SPORE FUNDING TO ENABLE INTEGRATED TEAMS THAT CAPITALIZE ON THE STRENGTHS OF THESE NEW AND ESTABLISHED INVESTIGATORS TO ACHIEVE OUR COMMON GOAL OF ELIMINATING LUNG CANCER DEATHS. THE OVERARCHING GOALS OF THIS SPORE ARE TO: A) DESIGN IMMUNOLOGIC THERAPIES THAT HARNESS BOTH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS TO OVERCOME ALK INHIBITOR RESISTANCE AND ENHANCE EFFICACY OF PD-1 IMMUNE CHECKPOINT BLOCKADE IN NON-SMALL CELL LUNG CANCER (NSCLC) (PROJECTS 1 AND 2); B) DEVELOP INNOVATIVE APPROACHES TO EGFR AND ALK-DRIVEN LUNG CANCER WITH POTENTIAL TO IMPROVE LONG TERM SURVIVAL VIA CANCER VACCINES OR ELIMINATION OF DRUG TOLERANT PERSISTER (DTP) CELLS OR CANCER VACCINES (PROJECTS 1 AND 3); C) CO-OPT VULNERABILITIES SUCH AS REPLICATION STRESS IN SMARCA4 MUTANT NSCLC OR A SENESCENCE PROGRAM IN EGFR TKI DTPS (PROJECTS 2 AND 3); D) FOSTER INTER-INSTITUTIONAL COLLABORATION, INCLUDING EXCHANGE OF LUNG CANCER MODELS AND PATIENT SAMPLES (ALL PROJECTS); AND E) CONTINUE TO SUPPORT AND DEVELOP THE NEXT GENERATION OF LUNG CANCER TRANSLATIONAL SCIENTISTS FROM OUR TALENTED GROUP OF FELLOWS AND EARLY CAREER INVESTIGATORS, WITH AN EMPHASIS ON INCREASING DIVERSITY AND EQUITY.

A TELEHEALTH ADVANCE CARE PLANNING INTERVENTION FOR COVID-19 IN NEW YORK CITY

SIMPRO RESEARCH CENTER: INTEGRATION AND IMPLEMENTATION OF PROS FOR SYMPTOM MANAGEMENT IN ONCOLOGY PRACTICE

TARGETING REPLICATION STRESS AND DNA DAMAGE RESPONSE IN UTERINE CANCER - PROJECT SUMMARY UTERINE CANCER (UC) INCIDENCE AND DEATH RATES ARE BOTH SIGNIFICANTLY INCREASING IN THE UNITED STATES. MOST UCS ARE ENDOMETRIAL CANCERS WHICH ARISE FROM THE INNER LINING OF THE UTERUS AND ARE DEFINED BY SEVERAL DIFFERENT HISTOLOGIC SUBTYPES, THE MOST COMMON OF WHICH IS ENDOMETRIOID. ADDITIONALLY, SURVIVAL OUTCOMES ARE WORSE FOR BLACK WOMEN. BECAUSE OF THE WORSENING SURVIVAL OF WOMEN WITH ADVANCED AND RELAPSED ENDOMETRIAL CANCER, THIS P01 GRANT IS FOCUSED ON TARGETING REPLICATION STRESS (RS) IN ORDER TO IMPROVE THERAPEUTIC OUTCOMES IN THESE PATIENTS. RS IS DEFINED AS THE SLOWING OR STALLING OF THE REPLICATION FORK PROGRESSION DURING DNA SYNTHESIS AND IS WIDELY RECOGNIZED AS A SIGNIFICANT CAUSE OF GENOMIC INSTABILITY AND A CRITICAL FEATURE OF CANCER CELLS. THIS P01 GRANT INVESTIGATES 3 DIFFERENT STRATEGIES FOR TARGETING RS IN UC WITH THE GOAL OF TRANSLATING THESE INTO EFFECTIVE SALVAGE THERAPIES FOR WOMEN WITH ADVANCED/RELAPSED UC. WE HAVE ASSEMBLED A TEAM OF INTERNATIONALLY RECOGNIZED RESEARCHERS FROM THE DANA-FARBER CANCER INSTITUTE AND THE BRIGHAM AND WOMEN’S HOSPITAL, BOTH IN BOSTON MA, WITH MULTIDISCIPLINARY EXPERTISE IN UC, DNA REPAIR AND RS, IMMUNOTHERAPY, PRECLINICAL MODELS, BIOSTATISTICS, COMPUTATIONAL BIOLOGY, GYNECOLOGIC PATHOLOGY, DRUG DEVELOPMENT AND CLINICAL TRIALS. THIS P01 GRANT IS BEING LED BY DRS. PANAGIOTIS KONSTANTINOPOULOS, JOYCE LIU, AND URSULA MATULONIS WHO ARE RECOGNIZED INTERNATIONAL LEADERS IN THE FIELD OF GYNECOLOGIC CANCER AND ENDOMETRIAL CANCER RESEARCH. THIS P01 GRANT CONSISTS OF 3 PROJECTS AND 4 CORES. THE LEADERSHIP TEAM FOR EACH PROJECT IS COMPRISED OF PAIRED INVESTIGATORS WITH COMPLEMENTARY EXPERTISE IN BASIC SCIENCE AND CLINICAL/TRANSLATIONAL RESEARCH. PROJECT 1 FOCUSES ON STUDYING THE MECHANISM OF WEE1 INHIBITION IN RECURRENT USC OR P53-MUTATED UCS AND THE CORRELATION OF WEE1 ACTIVITY WITH FUNCTIONAL AND IMMUNOHISTOCHEMICAL (IHC) MEASURES OF RS. BASED UPON THE RESULTS OF A CLINICAL TRIAL OF THE WEE1 INHIBITOR ADAVOSERTIB WHICH PREVIOUSLY DEMONSTRATED SIGNIFICANT CLINICAL ACTIVITY IN USCS, THIS PROJECT LEVERAGES A COLLECTION OF PATIENT-DERIVED XENOGRAFTS (PDXS), PATIENT-DERIVED ORGANOIDS (PDOS), AND GENETICALLY ENGINEERED MOUSE MODELS (GEMMS) OF P53-MUTATED/NULL ENDOMETRIAL CANCER TO EXAMINE THE EFFECTS OF WEE1 INHIBITION ON FUNCTIONAL AND IHC MEASURES OF RS IN THE IN VITRO AND IN VIVO SETTING. ADDITIONALLY, THROUGH A BIOPSY-DRIVEN INVESTIGATOR-INITIATED PROTOCOL OF THE WEE1 INHIBITOR ZN-C3 IN USC, PROJECT 1 WILL EXAMINE THE EFFECTS OF WEE1 INHIBITION ON MEASURES OF RS IN CO-CLINICAL PDOS AND CORRELATION OF THESE MEASURES WITH CLINICAL ACTIVITY. PROJECT 2 FOCUSES ON THE HYPOTHESIS THAT INHIBITION OF THE PI3K PATHWAY CAN INCREASE RS AND THEREFORE CREATE SYNERGY WITH ATR INHIBITORS. IN PREVIOUSLY PERFORMED PRISM AND CRISPR SCREENS, INHIBITION OF PI3K SIGNALING TOGETHER WITH ATR INHIBITION WAS IDENTIFIED AS POTENTIALLY SYNERGISTIC AND SUBSEQUENT EXPERIMENTS HAVE DEMONSTRATED SYNERGISM BETWEEN THE PI3K INHIBITOR COPANLISIB AND THE ATR INHIBITOR ELIMUSERTIB. PROJECT 2 WILL EXAMINE IN PDX, PDO, AND GEMM MODEL SYSTEMS THE POTENTIAL FOR SYNERGY BETWEEN ATR AND PI3K INHIBITION AND WILL EXPLORE THE CLINICAL ACTIVITY OF THIS COMBINATION IN A PHASE 1B DOSE ESCALATION CLINICAL TRIAL WITH DOSE EXPANSION IN UTERINE SEROUS AND ARID1A MUTATED UTERINE TUMORS, BOTH ENRICHED IN CONCOMITANT PI3K PATHWAY ALTERATIONS AND GENOMIC ALTERATIONS ASSOCIATED WITH HIGH RS. PROJECT 3 FOCUSES ON FURTHER INVESTIGATING PRELIMINARY DATA SHOWING THAT TARGETING THE RS RESPONSE THROUGH INHIBITION OF DNA DAMAGE CHECKPOINT KINASES ATR AND WEE1 LEADS TO INCREASED DNA DAMAGE AND ACTIVATION OF THE STING/TBK1/IRF3 PATHWAY, RESULTING IN ENHANCED ANTI-TUMOR IMMUNITY AND IMPROVED RESPONSE TO IMMUNE CHECKPOINT INHIBITION (ICI). BASED ON THESE, A NOVEL STRATEGY IS PROPOSED TO EXTEND THE BENEFIT OF IMMUNOTHERAPY IN MISMATCH REPAIR PROFICIENT (MMRP) CANCERS BY USING DNA DAMAGE CHECKPOINT KINASE INHIBITORS IN COMBINATION WITH ICIS. THE MAIN HYPOTHESIS IS THAT PRIMING THE IMMUNOLOGICALLY “COLD” MMRP UCS INTO “HOT” TUMORS USING DNA DAMAGE CHECKPOINT KINASE INHIBITION, COMBINED WITH ICIS TO OVERCOME TUMOR-MEDIATED IMMUNOSUPPRESSION, WILL LEAD TO EFFECTIVE ANTITUMOR IMMUNITY AGAINST MMRP UCS. THE 4 CORES IN THIS GRANT INCLUDE ADMINISTRATIVE; BIOSTATISTICS AND COMPUTATIONAL BIOLOGY; PRECLINICAL MODEL SYSTEMS; AND PATHOLOGY. REVIEW OF OUR P01 GRANT EXTERNAL TO THE PROJECT AND CORE TEAMS WILL OCCUR THROUGH AN EXTERNAL ADVISORY BOARD (EAB), AN INTERNAL ADVISORY BOARD (IAB), AND AN ADVOCATE CORE.

INFORMED COMBINATION STRATEGIES FOR PERIPHERAL T-CELL LYMPHOMAS

NEW THERAPEUTIC VULNERABILITIES IN BREAST CANCER

NCTN LEAD ACADEMIC PARTICIPATING SITE AT DANA-FARBER/PARTNERS CANCER CARE

MOLECULAR PHENOTYPING OF ~100,000 CODING VARIANTS ACROSS MENDELIAN DISEASE GENES - ABSTRACT THE LAST FOUR DECADES HAVE PRODUCED AN ENORMOUS CATALOG OF HUMAN GENOMIC VARIANTS WHICH HAS THE POTENTIAL TO REVOLUTIONIZE HUMAN GENETICS. AMONG THE VARIANTS IDENTIFIED IN THE HUMAN “VARIOME” SO FAR, SOME APPEAR BENIGN, I.E. THEY DON’T SEEM TO CONFER ANY PARTICULAR PHENOTYPE, A SIGNIFICANT PROPORTION ARE ASSOCIATED OR POTENTIALLY ASSOCIATED WITH ONE OR MORE GENETICALLY INHERITED DISORDERS, BUT AN EVEN GREATER PERCENTAGE OF OBSERVED HUMAN VARIANTS, 99% OF MISSENSE VARIANTS, REMAIN UNINTERPRETED OR ANNOTATED AS VARIANTS OF UNKNOWN SIGNIFICANCE (VUSS). TO TRANSLATE THIS HUGE AMOUNT OF GENETIC INFORMATION INTO GENERAL PRINCIPLES UNDERLYING GENOTYPE-PHENOTYPE RELATIONSHIPS AS WELL AS MOLECULAR MECHANISMS RESPONSIBLE FOR THE DEVELOPMENT OF INHERITED DISEASE, THERE IS AN URGENT NEED FOR LARGE-SCALE, SYSTEMATIC, HIGH THROUGHPUT “FUNCTIONAL CHARACTERIZATION” PROJECTS SUCH AS THOSE ENVISIONED WITHIN THE NEW “IMPACT OF GENOMIC VARIATION ON FUNCTION” (IGVF) CONSORTIUM PROPOSED BY NHGRI. ALTHOUGH MOST MONOGENIC MENDELIAN DISORDERS ARE INDIVIDUALLY RARE, WHEN COMBINED THESE DISEASES AFFECT 20 MILLION AMERICANS. THE CLINVAR DATABASE DESCRIBES WITHIN 3,671 MENDELIAN DISEASE GENES OVER 260,000 MISSENSE VARIANTS CLASSIFIED AS PATHOGENIC, BENIGN, OR VUSS. WE CURRENTLY LACK STRONG AND COMPREHENSIVE EVIDENCE TO SYSTEMATICALLY ANALYZE CODING VARIANTS ACROSS THE SPECTRUM OF HUMAN MENDELIAN DISEASES. WE PROPOSE TO FUNCTIONALLY CHARACTERIZE ~100,000 VARIANTS ACROSS MOST OF THE KNOWN MENDELIAN DISEASE- ASSOCIATED GENES BY COMPARING WILD-TYPE, OR “REFERENCE”, GENE PRODUCTS AND THEIR CORRESPONDING VARIANTS FOR A RICH ARRAY OF FUNDAMENTAL PROTEIN PROPERTIES AND PHENOTYPIC IMPACTS, INCLUDING PROTEIN STABILITY (EXPRESSION), SUBCELLULAR LOCALIZATION, CELL VIABILITY, CELL MORPHOLOGY, AND THE ABILITY TO MEDIATE MACROMOLECULAR INTERACTIONS WITH PROTEIN PARTNERS. OUR VARIANT CHARACTERIZATION ACROSS THE MENDELIAN PROTEOME (VARCHAMP) CENTER WILL GENERATE A SEARCHABLE AND WIDELY AVAILABLE CATALOG OF THESE VARIANT EFFECTS VIA THE IGVF DATA AND ADMINISTRATIVE COORDINATING CENTERS (DACCS), AND ASSIST IN THE “PREDICTIVE MODELING PROJECTS” TO CARRY OUT VARIANT EFFECT PREDICTIVE MODELING USING THIS DATA. IN ADDITION TO PROVIDING A RICH SOURCE OF FUNCTIONAL INFORMATION ON TENS OF THOUSANDS OF GENOMIC VARIANTS IN THE NEXT FIVE YEARS, ALL OF OUR CONCEPTS, TECHNOLOGIES AND RESOURCES GENERATED DURING THIS PROJECT ARE EXPORTABLE AND WILL BE SHARED TO ENABLE OTHERS, BOTH INSIDE AND OUTSIDE THE IGVF CONSORTIUM, TO LEVERAGE OUR APPROACH IN THEIR OWN STUDIES AND EXPAND THE CATALOG.

HUMAN CANCER SUPPRESSOR FUNCTIONS OF PROTEIN PHOSPHATASE 2A

A PLANT INTERACTOME NETWORK MAP

MOLECULAR MECHANISMS OF FATE CHOICE IN NEURAL STEM CELLS

THERAPEUTIC OPPORTUNITIES FOR PEDIATRIC ASTROCYTOMA

THE DANA-FARBER CANCER INSTITUTE CANCER TARGET DISCOVERY AND DEVELOPMENT CENTER

CIRCULATING BIOMARKER CONSORTIUM FOR PANCREATIC CANCER EARLY DETECTION

ROLE OF TIM FAMILY GENES IN ASTHMA AND ALLERGIC DISEASES

ORTHOPOX IMMUNIZATION IN PATIENTS WITH CANCER OR ECZEMA

EARLY CLINICAL TRIALS OF NEW ANTI-CANCER AGENTS WITH PHASE I EMPHASIS

STRUCTURE, MECHANISM, AND PHARMACOLOGY OF BRAF AND ITS PARTNERS IN THE RAS/RAF/MAP KINASE PATHWAY

INTEGRATING TRANSFORMING APPROACHES TO IDENTIFY AND TARGET NEW VULNERABILITIES IN CANCER

THE USE OF WHOLE-EXOME SEQUENCING TO GUIDE THE CARE OF CANCER PATIENTS

MECHANISMS AND VULNERABILITIES OF ABERRANT TRANSCRIPTIONAL ENHANCERS IN CANCER

A HIGH EFFICIENCY IMAGER FOR REAL-TIME LUNG CANCER MONITORING DURING RADIOTHERAPY

THE DREAM B-MYB-MUVB COMPLEX CONTROLS SENSITIVITY TO DNA REPLICATION ACTIVATORS AND INHIBITORS

DEVELOPMENT OF COMBINATION THERAPIES TO DELAY/PREVENT ACQUIRED DRUG RESISTANCE

MAXIMIZING THE EFFECTIVENESS OF PI3K INHIBITORS IN THE TREATMENT OF PTEN CANCERS

RESEARCH TRAINING IN PEDIATRIC ONCOLOGY

DF/HCC PROSTATE SPORE - PROJECT SUMMARY – OVERALL THE DANA-FARBER/HARVARD CANCER CENTER (DF/HCC) PROSTATE SPORE SEEKS TO IMPROVE THE UNDERSTANDING AND TREATMENT OF PROSTATE CANCER USING A HIGHLY TRANSLATIONAL APPROACH. THE APPLICATION CONSISTS OF THREE PROJECTS, THREE CORES, A DEVELOPMENTAL RESEARCH PROGRAM AND A CAREER ENHANCEMENT PROGRAM. THE SPORE INFRASTRUCTURE WILL FACILITATE INTERACTIONS AND COLLABORATION WITHIN OUR THRIVING COMMUNITY OF BASIC, CLINICAL, AND POPULATION SCIENCE RESEARCHERS DEDICATED TO PROSTATE CANCER RESEARCH. EACH PROJECT ADDRESSES A FUNDAMENTAL CHALLENGE THAT CONTRIBUTES TO PROSTATE CANCER MORBIDITY AND MORTALITY. PROJECT 1 LEVERAGES TUMOR SPECIMENS FROM PATIENTS WITH HIGH-RISK PROSTATE CANCER TREATED WITH NEOADJUVANT THERAPIES TO UNDERSTAND HOW TUMORS RESPOND AND RESIST ACUTE POTENT ANDROGEN RECEPTOR BLOCKADE AND TO DEVELOP NOVEL STRATEGIES TO IMPROVE CURE RATES AND COMBAT RESISTANCE. PROJECT 2 WILL DEVELOP INNOVATIVE STRATEGIES TO TARGET THE EPIGENOME IN LATER STAGES OF ADVANCED CASTRATION RESISTANT PROSTATE CANCER AND WILL DEVELOP A FIRST-IN-FIELD CLINICAL TRIAL FOCUSED ON CO-TARGETING EZH2 AND PARP. PROJECT 3 DELVES DEEP INTO BIOMARKERS IN LOCALIZED PROSTATE CANCER, LEVERAGING INNOVATIONS IN COMPUTATION AND BIOLOGICALLY-GUIDED DEEP LEARNING, TO DELIVER ON PRECISION CANCER MEDICINE IN THIS DISEASE STATE. THE ABILITY TO UNDERSTAND WHY SOME LOCALIZED PROSTATE CANCERS ARE PHENOTYPICALLY AGGRESSIVE AND PREDICT WHICH LOCALIZED PROSTATE CANCERS WILL BEHAVE IN THIS MANNER ADDRESSES A LARGE CLINICAL UNMET NEED. EACH OF THESE PROJECTS COMBINES ELEGANT PRECLINICAL WORK WITH INNOVATIVE CLINICAL STUDIES LED BY DF/HCC INVESTIGATORS. CORE A, THE ADMINISTRATIVE CORE, WILL BE THE CENTER FOR SCIENTIFIC, FISCAL AND ADMINISTRATIVE OVERSIGHT. IT WILL LEAD EFFORTS IN PLANNING AND COMMUNICATION, AND ALSO HOUSE THE PATIENT ADVOCACY COMMITTEE. CORE A WILL ENSURE THAT THE DF/HCC INFRASTRUCTURE SUPPORTS THE SPORE CLINICAL AND TRANSLATIONAL RESEARCH EFFORTS. CORE B, THE BIOSTATISTICS AND COMPUTATIONAL BIOLOGY CORE, WILL PROVIDE SPECIALIZED EXPERTISE IN BIOSTATISTICS AND THE MANAGEMENT OF GENOMIC AND OTHER NEXT GENERATION SEQUENCING DATA AND DATA SHARING. CORE C, THE BIOSPECIMEN AND PATHOLOGY CORE, WILL MAINTAIN TISSUE/BLOOD REPOSITORIES FOR THE SPORE PROJECTS AS WELL AS OTHER INVESTIGATORS WITHIN THE PROSTATE CANCER PROGRAM. IT WILL PROVIDE CRITICAL EXPERTISE AND PATHOLOGY SERVICES INCLUDING NEXT GENERATION MOLECULAR ASSAYS AND WILL HELP FACILITATE THE USE OF FRESH TUMOR SPECIMENS INCLUDING RAPID AUTOPSIES FOR PATIENT DERIVED MODEL DEVELOPMENT TO ACCELERATE TRANSLATIONAL INVESTIGATION. THE DEVELOPMENTAL RESEARCH AND CAREER ENHANCEMENT PROGRAMS WILL IDENTIFY AND FUND INNOVATIVE PROJECTS THAT ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH QUESTIONS AND UNMET NEEDS IN PROSTATE CANCER AND WILL SUPPORT EARLY CAREER AND NEW PROSTATE CANCER INVESTIGATORS. THESE PROGRAMS WILL ACTIVELY RECRUIT AND RETAIN RESEARCHERS FROM DIVERSE BACKGROUNDS TO FOSTER CUTTING-EDGE AND IMPACTFUL PROSTATE CANCER TRANSLATIONAL SCIENCE. WE ANTICIPATE THAT THE DF/HCC PROSTATE SPORE WILL MAKE SUBSTANTIAL SCIENTIFIC DISCOVERIES IN THE FIELD AND TRANSLATE DIRECTLY INTO BENEFITS FOR MEN WITH PROSTATE CANCER.

BIOCONDUCTOR: AN OPEN-SOURCE, OPEN-DEVELOPMENT COMPUTING RESOURCE FOR GENOMICS - PROJECT SUMMARY BIOCONDUCTOR IS A PROJECT DEDICATED TO THE ANALYSIS AND INTERPRETATION OF HIGH THROUGHPUT GENOMIC DATA, INCLUD- ING SEQUENCING, MICROARRAY, OW CYTOMETRY, PROTEOMICS, AND IMAGING DATA. BIOCONDUCTOR IS BASED ON THE R STA- TISTICAL PROGRAMMING LANGUAGE. IT CONSISTS OF SOFTWARE, ANNOTATION, AND DATA PACKAGES DEVELOPED AND CONTRIBUTED BY INDIVIDUALS FUNDED BY THIS GRANT, AND BY THE NATIONAL AND INTERNATIONAL SCIENTIC COMMUNITY. BIOCONDUCTOR IS HIGHLY RESPECTED, WIDELY USED IN THE GLOBAL BIOINFORMATICS COMMUNITY, HIGHLY CITED, AND HAS FORMAL COLLABORATIVE ALIGNMENTS WITH THE HUMAN CELL ATLAS AND NHGRI'S GENOMIC ANALYSIS, VISUALIZATION, AND INFORMATICS LAB SPACE (ANVIL). WORK PROPOSED IN THIS RENEWAL APPLICATION REECTS THE COMMITMENT OF THE PROJECT TO OPEN-SOURCE/OPEN- DEVELOPMENT CREATION AND DISTRIBUTION OF PORTABLE TOOLS FOR GENOMIC DATA SCIENCE, HIGH-QUALITY DOCUMENTATION AND SUPPORT FOR USERS AND DEVELOPERS, ADAPTATION OF COMPUTATIONAL METHODS TO NEW TECHNOLOGIES FOR CLOUD-SCALE DATA SCIENCE, AND EFFECTIVE TRAINING OF THE WORKFORCE FOR GENOME BIOLOGY AND PERSONALIZED GENOMIC MEDICINE. THE SPE- CIC AIMS ARE (1) MAINTENANCE AND ENHANCEMENT OF THE SYSTEM AT BIOCONDUCTOR.ORG FOR ORGANIZING AND DISTRIBUTING ANALYTIC SOFTWARE, REFERENCE DATA, AND CURATED EXPERIMENTAL DATA, (2) HARDENING OF CORE INFRASTRUCTURAL SOFTWARE PACKAGES TO INCREASE RELIABILITY AND THROUGHPUT OF ANALYSES BASED ON THE SYSTEM, (3) CONDUCT RESEARCH AND DEVEL- OPMENT OF BEST PRACTICES FOR TAKING ADVANTAGE OF SCALABLE COMPUTING STRATEGIES FOR INTEGRATIVE CLOUD-SCALE GENOMIC ANALYSIS, AND (4) ENHANCE COMMUNITY ENGAGEMENT AND EDUCATION PRACTICES THAT HAVE BEEN INTRINSIC TO THE PROJECT SINCE ITS INCEPTION. BY PURSUING THESE AIMS, PROJECT INVESTIGATORS AND CONTRIBUTORS ADD TO THE USABILITY, RELEVANCE, AND ROBUSTNESS OF A SYSTEM AND COMMUNITY THAT IS UNIQUE AND IS UNIQUELY SITUATED TO ACCELERATE PROGRESS IN MANY AREAS OF GENOMIC DATA SCIENCE, ULTIMATELY CONTRIBUTING TO BIOLOGICAL KNOWLEDGE AND IMPROVEMENT OF HUMAN HEALTH.

ONCOGENIC SIGNALING BY DF3/MUC1 IN HUMAN BREAST CANCER

GENETIC EVOLUTION OF GLIOBLASTOMAS DURING RADIATION AND TEMOZOLOMIDE THERAPY

CPVOD-19 DEVELOPMENT OF DF-COV FOR THE TREATMENT AND PREVENTION OF COVID-19 AND ASSOCIATED IMMUNOPATHOLOGIC RESPIRATORY COMPLICATIONS

RNA-BASED HIV-1 CHIMERA VACCINES ENCODING A TRIMERIZING HOST SELF-PROTEIN PROTOMER LINKED TO A VIRAL MPER-TM SEGMENT - SUMMARY – OVERALL WHILE THERE IS AN URGENT NEED FOR VACCINES ELICITING BROADLY NEUTRALIZING ANTIBODIES (BNABS) AGAINST THE HIGHLY MUTABLE HIV-1 RETROVIRUS TO STEM ITS GLOBAL SPREAD, THIS GOAL REMAINS ELUSIVE. ANTIBODIES PRODUCED AGAINST TRIMERIC GP160 SITES OF VULNERABILITY DURING NATURAL INFECTION DRIVE RETROVIRAL MUTATION FURTHER, DIVERSIFYING QUASI- SPECIES IN INDIVIDUALS. ONE APPARENT EXCEPTION IS THE CONSERVED MEMBRANE-PROXIMAL EXTERNAL REGION (MPER) SITE, CRITICAL FOR HEMIFUSION/FUSION AND WHICH IS STEALTH, LARGELY IMMERSED IN LIPID AND ONLY TRANSIENTLY REVEALED DURING SPONTANEOUS ECTODOMAIN TILTING. LIPOSOME-ARRAYED MPER SEGMENTS INDUCE SPECIFIC ANTIBODIES IN MICE BUT WITHOUT NEUTRALIZING ACTIVITY, EXPLAINED BY THE RESTRICTED ANTIBODY ACCESS TO THE NATIVE MPER RESIDING IN A NARROW “CRAWLSPACE” BETWEEN THE VIRAL MEMBRANE BELOW AND THE BASE OF THE GP120 AND GP41 PROTOMERS OF THE TRIMERIC GP160 ENVELOP. BIOMATERIAL FORMULATION OF POLYMER “STERIC CLOUDS” ON LIPOSOMES OR ALTERNATIVE ORIGAMI- BASED APPROACHES ON NANODISCS TO LIMIT ACCESS TO THE MPER, AKIN TO THAT MANDATED BY THE TRIMER THREE-FOLD AXIS, WERE TECHNICALLY CUMBERSOME AND CONFOUNDED BY THE UNCERTAINTY OF MPER TOPOLOGY. OUR RECENT ANALYSIS OF THE STRUCTURE AND DYNAMICS OF NANODISC-EMBEDDED TRIMERIC HIV-1 SPIKE PROTEIN PROVIDES COMPELLING DATA FOR ALTERNATIVE DESIGN. IN ADDITION, SYNTHETIC RNA LIPID NANOPARTICLE (LNP) ENCAPSULATION TECHNOLOGY OBVIATES VACCINE CHALLENGES WITH HYDROPHOBIC PROTEINS SUCH AS THE MPER AND ADJACENT TRANSMEMBRANE SEGMENT (MPER-TM). THIS P01 COMPRISES TWO PROJECTS. PROJECT 1 SHALL DETERMINE THE IMMUNOGENICITY OF RNA VACCINES ENCODING MPER-TM TRIMERS FUSED TO STRUCTURALLY SUITABLE SELF-PROTEINS TO FOCUS ANTIBODY RESPONSES AGAINST THE CONJOINT MEMBRANE ARRAYED VIRAL MPER-TM, WITH THE SELF-PROTEINS IMPOSING STERIC RESTRICTION COMPARABLE TO THAT EXERTED BY THE GP160 ECTODOMAIN ON THE NATIVE MPER. SEROLOGICAL, SINGLE B CELL, RECOMBINANT MAB METHODS, NEUTRALIZATION ASSAYS AND IG BIOINFORMATIC ANALYSES ARE APPLIED. AUTOMATED COMPUTATIONAL SEARCHES OF THE PDB INFORMED BY SINGLE-PARTICLE CRYO-ELECTRON MICROSCOPY (CRYO-EM) STRUCTURES AND USING RNA TECHNOLOGY REVEAL ANTIGENICITY AND IMMUNOGENICITY OF CONSTRUCT DESIGN FOR PLANNED IMMUNIZATION STUDIES IN NORMAL AS WELL AS KNOCK- IN MICE HARBORING HUMAN IG D3-3 AND JH6 GENE SEGMENTS FOR LONG CDRH3 LOOP GENERATION. PROJECT 2 WILL PERFORM CRYO-EM AND X-RAY CRYSTALLOGRAPHIC STUDIES TO COMPARE EXISTING AND ADDITIONAL HIV-1 PATIENT-DERIVED BNABS OBTAINED FROM BIOBANKED SERIAL SAMPLES (OSIER, IAVI) WITH THOSE THAT ARE VACCINE ELICITED, IN THE CONTEXT OF NANODISC-ARRAYED MPER IMMUNOGENS AND NATIVE SPIKE PROTEIN. WE SHALL INVESTIGATE IG REQUIREMENTS OF SOMATIC HYPERMUTATION (SHM), FAB MOLECULAR DYNAMICS (MD) AND CO-EVOLUTION OF ANTIBODY APPROACH ANGLES AND AFFINITIES OF BNABS OF IGG1 AND IGG3 ISOTYPES. PROJECTS 1 & 2 SHALL BE PERFORMED BY KIM/WEISSMAN (DFCI/UPENN) AND REINHERZ (DFCI), RESPECTIVELY, WITH FOUR TECHNOLOGY COMPONENTS: MRNA-LNP VACCINE SYNTHESIS BY WEISSMAN (U PENN); CRYO-EM BY WALZ (ROCKEFELLER), X-RAY CRYSTALLOGRAPHY BY TAN (APS) AND KWONG (NIH); AND MD BY HUANG (TEXAS A&M). ADMINISTRATIVE (REINHERZ) AND ANTIBODY (SEAMAN, BIDMC) CORES SERVE ALL.

CANCER IMMUNOLOGIC DATA COMMONS

IMMUNOLOGIC MECHANISMS THAT PREVENT AUTOIMMUNITY

CONFORMATIONAL LANDSCAPE OF THE HIV-1 ENVELOPE GLYCOPROTEINS

FUNCTIONAL ANNOTATION OF CANCER GENOMES: TCGA, GLIOBLASTOMA AND OVARIAN CANCER

HIV-1 ENVELOPE GLYCOPROTEINS

READING MITOCHONDRIAL APOPTOTIC SIGNALING TO IDENTIFY ACTIVE CANCER THERAPEUTICS

CROSSPROTECTIVE CTL AGAINST INFLUENZA

HIV-1 INTEGRASE STRUCTURAL BIOLOGY

NCTN LEAD ACADEMIC PARTICIPATING SITE AT DANA-FARBER/PARTNERS CANCER CARE

GENOMIC DIVERSITY OF PROSTATE CANCER ACROSS THE AFRICAN DIASPORA - PROJECT SUMMARY/ABSTRACT AFRICAN DESCENT MEN (ADM) ACROSS THE AFRICAN DIASPORA HAVE THE HIGHEST RATES OF PROSTATE CANCER (CAP) OF ANY RACIAL OR ETHNIC GROUP. THE INCIDENCE RATE IN AFRICAN AMERICAN MEN (AAM) IS 71% HIGHER THAN IN EUROPEAN AMERICAN MEN (EAM) AND THE AAM MORTALITY RATE IS 210% HIGHER THAN EAM. DESPITE THE PUBLIC HEALTH IMPLICATIONS OF THESE OBSERVATIONS, THE UNDERLYING CAUSES OF THIS DISPARITY REMAIN UNRESOLVED. THERE IS SUBSTANTIAL EVIDENCE THAT SOCIAL INEQUITIES AND ACCESS TO HEALTH CARE ARE IN PART RESPONSIBLE FOR CAP DISPARITIES. THERE IS LIMITED CONSISTENT EVIDENCE FOR EXPOSURES AND ENVIRONMENTAL FACTORS IN CAP ETIOLOGY OR PROGRESSION. IN CONTRAST, CAP IS STRONGLY INFLUENCED BY INHERITED GENETIC VARIATION, AND THERE IS GROWING EVIDENCE THAT THE MUTATIONAL LANDSCAPE OF PROSTATE TUMORS VARIES SUBSTANTIALLY BY RACE. THESE OBSERVATIONS SUGGEST THAT BIOLOGICAL FACTORS INFLUENCE CAP INCIDENCE AND TUMOR AGGRESSIVENESS DIFFERENTIALLY BY RACE AND MAY IN PART EXPLAIN CAP DISPARITIES BY RACE. TO INFORM THE BIOLOGICAL BASIS OF CAP DISPARITIES THAT ADVERSELY AFFECT ADM, WE HAVE DEVELOPED A LARGE, MULTICENTER CONSORTIUM KNOWN AS “MEN OF AFRICAN DESCENT AND CARCINOMA OF THE PROSTATE” (MADCAP). USING THE RESOURCES OF THIS CONSORTIUM, WE PROPOSE TO UNDERTAKE A STUDY OF CAP IN ADM TO ADDRESS THE FOLLOWING AIMS: AIM 1: IDENTIFY COMMON GENETIC VARIANTS ASSOCIATED WITH CAP AGGRESSIVENESS IN ADM; AIM 2: DEFINE HISTOPATHOLOGICAL COMMONALITIES OF PROSTATE TUMORS IN ADM; AND AIM 3: EVALUATE MOLECULAR SIGNATURES AND SUBTYPES IN PROSTATE TUMORS AND DETERMINE THEIR RELATIONSHIP TO PATHOLOGICAL AND CLINICAL CHARACTERISTICS IN ADM. THE PROPOSED RESEARCH WILL HAVE INNOVATIVE IMPACT IN A NUMBER OF WAYS. WE WILL ADDRESS THE CRITICAL NEED FOR INCREASED ETHNIC DIVERSITY IN CANCER GENOMICS DATA, WHICH TO DATE HAS BEEN DOMINATED BY STUDIES IN EUROPEAN ANCESTRAL POPULATIONS. ETHNICALLY DIVERSE GENETIC DATA WILL NOT ONLY IMPROVE OUR UNDERSTANDING OF GENOMIC CONTRIBUTORS TO CANCER ETIOLOGY AND DISPARITIES BUT WILL ALSO AID IN THE DEVELOPMENT AND IMPLEMENTATION OF CANCER GENOMIC ANALYSIS FOR ALL POPULATIONS, REDUCE THE POTENTIAL FOR ERRORS IN DETERMINING PATHOGENICITY OF GENETIC SUSCEPTIBILITY VARIANTS, AND IMPROVE INTERPRETATION OF CANCER RISK IN ALL POPULATIONS INCLUDING AAM. IN UNDERTAKING THIS RESEARCH, WE WILL ENHANCE INFRASTRUCTURE NEEDED TO UNDERTAKE GENOMICS RESEARCH IN AFRICA THAT INCLUDES A LARGE, WELL-ANNOTATED SAMPLE OF SYSTEMATICALLY COLLECTED TUMORS WITH CLINICAL AND EPIDEMIOLOGIC DATA THAT CAN BE USED TO ADDRESS A VARIETY OF RESEARCH AND CLINICAL QUESTIONS. WE HAVE CONSTRUCTED THE MADCAP RESOURCES TO INTEGRATE DIRECTLY WITH EXISTING PUBLICLY AVAILABLE DATABASES, SUCH AS TCGA/ICGC AND GENIE, TO ENSURE THE AFRICAN DATA CAN BE READILY COMPARED WITH DATA FROM OTHER SOURCES. OUR DATA WILL ALSO INCLUDE DEEP PATHOLOGY, CLINICAL AND RISK FACTOR ANNOTATION, LARGELY UNAVAILABLE IN CURRENT PUBLIC DATASETS, TO PROVIDE A FULLER POTENTIAL TO UNDERSTAND UNDERLYING DISPARITIES IN CAP ETIOLOGY.

FUNCTIONAL ROLE OF THE MUC1-C ONCOPROTEIN IN NON-SMALL CELL LUNG CANCER

EPIGENETIC PLASTICITY IN TUMOR INITIATION AND EVOLUTION

IDENTIFICATION OF METABOLIC AND IMMUNE DEFICITS IN THE AGED POPULATION AND THEIR RESTORATION TO ACHIEVE YOUTHFUL ANTI-INFLUENZA VACCINE RESPONSIVENESS - PROJECT SUMMARY INFLUENZA IS A LEADING CAUSE OF DEATH IN THE ELDERLY AND CURRENT VACCINES ONLY PROTECT A FRACTION OF THIS POPULATION DESPITE WIDESPREAD VACCINATION PROGRAMS AND SPECIALIZED FORMULATIONS. A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS THAT CONTROL IMMUNOLOGICAL AGING IS URGENTLY NEEDED SO THAT NEWLY DESIGNED VACCINES, ADJUVANTS AND PHARMACOLOGIC INTERVENTIONS CAN BE EMPLOYED TO RESTORE YOUTHFUL ANTIBODY (AB) RESPONSES IN THE OLDER POPULATION. OUR OVERARCHING GOALS ARE FOCUSED ON DETERMINING THE EFFECTS OF AGING ON IMMUNE CELLS THAT MEDIATE THE ANTI-INFLUENZA AB VACCINE RESPONSE. WE WILL PERFORM AN INTEGRATED AND COMPREHENSIVE EVALUATION OF CIRCULATING T FOLLICULAR HELPER (TFH), T FOLLICULAR REGULATORY (TFR) CELLS AND B CELLS AS WELL AS THEIR SUBSETS FROM YOUNG AND OLDER INDIVIDUALS PRIOR TO AND AFTER SEASONAL INFLUENZA VACCINATION. WE WILL TEST THE HYPOTHESIS THAT A CONSEQUENCE OF ADVANCING AGE IS AN ALTERED DISTRIBUTION OF INDIVIDUAL SUBSETS OF TFH/TFR CELLS RESULTING IN METABOLIC REPROGRAMMING AND DEFECTIVE B CELL ELICITED INFLUENZA VACCINE RESPONSES. OUR INTEGRATED ANALYSIS INCLUDES STUDIES TO INVESTIGATE AT THE ORGANISMAL AND CELLULAR LEVEL AGE-RELATED DECLINES IN METABOLIC PATHWAYS, SUCH AS DEFECTIVE MITOCHONDRIAL BIOGENESIS AND ONE CARBON METABOLISM AND TO DETERMINE IF THESE CHANGES CONTRIBUTE TO THE IMMUNE DYSFUNCTION. FINALLY, KNOWLEDGE GAINED FROM THESE STUDIES WILL BE USED TO PERFORM PROOF OF CONCEPT RESCUE EXPERIMENTS IN VITRO TO RESTORE OPTIMAL INFLUENZA VACCINE RESPONSIVENESS. TO SUPPORT THESE STUDIES, SAMPLES WILL BE USED FROM A SEASONAL INFLUENZA VACCINEE COHORT OF 153 PARTICIPANTS (AGES 21-76, INCLUDING 15 INDIVIDUALS = 65YR) WHO HAVE DONATED BLOOD AT DAYS 0, 7 AND 32 AFTER QUADRIVALENT HEMAGGLUTININ (HA) VACCINATION. WE PLAN A TARGETED EXPANSION OF THIS COHORT TO RECRUIT AN ADDITIONAL 100 DONORS = 65 YEARS OF AGE AND A GROUP OF 25 YOUNGER ADULTS (= 40YR, N=25) FOR SINGLE CELL GENOMIC AND METABOLOMIC STUDIES THAT REQUIRE FRESH BLOOD SAMPLES. WE WILL TEMPORALLY FOLLOW THE INFLUENZA VACCINE RESPONSE AND COMPARE YOUNG AND OLDER GROUPS. SPECIFICALLY, IN AIM 1 WE WILL EXAMINE ALTERATIONS IN SUBSET COMPOSITION AND METABOLIC REPROGRAMMING IN FOLLICULAR T CELLS IN YOUNG AND AGED INDIVIDUALS. THE COMPLETION OF THESE STUDIES WILL ALLOW US TO UNDERSTAND WHETHER DEFECTS IN HUMORAL IMMUNITY ASSOCIATED WITH AGING ARE MEDIATED BY CHANGES IN TFH AND TFR SUBSETS, INTRINSIC FUNCTIONALITY, OR BOTH. IN AIM 2 WE WILL ASSESS CHARACTERISTICS OF THE AB RESPONSE AND DETERMINE COMPOSITION AND METABOLIC CHANGES IN B CELL POPULATIONS IN YOUNG AND AGED INDIVIDUALS. AT THE COMPLETION OF THESE STUDIES WE WILL ALSO UNDERSTAND CHANGES THAT RESULT IN IMMUNE IMPRINTING. IN AIM 3 WE WILL ANALYZE AGE- RELATED DYSFUNCTION OF TFH, TFR AND B CELLS IN VITRO IN RESPONSE TO INFLUENZA VACCINE ANTIGENS. TFH/B CELL CO-CULTURES WILL BE TREATED WITH IMMUNE MODULATORS AND SMALL MOLECULES TO RESTORE IMMUNOLOGIC AND METABOLIC FUNCTION TO OVERCOME AGE-RELATED DEFECTS IN VACCINE RESPONSES. WE HAVE ASSEMBLED A HIGHLY ACCOMPLISHED TEAM TO CARRY OUT THESE STUDIES WITH THE GOAL OF TESTING NEW PARADIGMS AND ESTABLISHING AN ACTIONABLE ROADMAP ON HOW TO IMPROVE VACCINE RESPONSIVENESS IN THE ELDERLY.

THE CENTER FOR SYNOVIAL SARCOMA BIOLOGY AND THERAPEUTICS

(PQ9) THE ROLE OF BCLW (BCL2L2) IN PREVENTING CHEMOTHERAPY INDUCED NEUROPATHY

THE DUAL ROLE OF PRO-APOPTOTIC BAD IN INSULIN SECRETION AND BETA CELL SURVIVAL

HEDGEHOG SIGNALING IN EARLY DEVELOPMENT OF THE GASTROINTESTINAL TRACT

FUNCTIONAL GENOMIC DISSECTION OF REFRACTORY ANEMIA

MYELOMA MULTIDIMENSIONAL PRECANCER ATLAS - SUMMARY MULTIPLE MYELOMA (MM) IS ALMOST ALWAYS PRECEDED BY MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) AND SMOLDERING MYELOMA (SMM), WITH A TRANSFORMATION RATE OF ~1% AND ~10% PER YEAR, RESPECTIVELY. LARGE RACIAL DISPARITIES EXIST IN MM AND ITS PREMALIGNANT CONDITIONS; COMPARED TO WHITES, AFRICAN-AMERICANS HAVE A TWO-FOLD INCREASED PREVALENCE OF MGUS/MM AND ARE DIAGNOSED WITH MM AT YOUNGER AGES. WHAT IS LACKING IS THE IDENTIFICATION OF THE TRUE TRANSITION STEPS THAT OCCUR FROM EARLY PRECANCEROUS STAGES TO OVERT MM AND IDENTIFYING THE BIOLOGICAL PRECANCER STAGES OF THE DISEASE. HERE, WE PROPOSE TO CONSTRUCT THE MYELOMA MULTIDIMENSIONAL PRE-CANCER ATLAS (MMPCA). WE BELIEVE THAT THE IDENTIFICATION OF THE TRANSITION STAGES ALONG THE SPECTRUM OF HEALTHY, PRECURSOR MM TO OVERT MM IN A RACIALLY DIVERSE POPULATION REPRESENTS A MISSED OPPORTUNITY TO FULLY INFORM DISEASE CHARACTERIZATION, MONITORING, AND POTENTIAL NEEDS FOR PATIENTS TO RECEIVE EARLY INTERVENTION THERAPIES. WE WILL LEVERAGE OUR LARGE COLLECTION OF SAMPLES FROM TWO COHORT STUDIES THAT ARE RACIALLY DIVERSE WITH OVER 30% AFRICAN OR AFRICAN AMERICANS AND WITH OVER 10,000 SAMPLES COLLECTED SERIALLY OVER THE LAST 10 YEARS; AND WITH WELL-ANNOTATED DATA OF DISEASE PROGRESSION. OUR OVERARCHING HYPOTHESIS IS THAT MALIGNANT TRANSFORMATION OCCURS THROUGH THE COOPERATIVE ACQUISITION OF GENOMIC AND MICROENVIRONMENT ALTERATIONS THAT OCCUR IN A SUSCEPTIBLE HOST ENVIRONMENT. THE MMPCA WILL CREATE A COMPREHENSIVE SPATIAL AND TEMPORAL ATLAS OF PRECURSOR MM TO UNDERSTAND GENOMIC AND MICROENVIRONMENTAL ALTERATIONS ACROSS THE SPECTRUM OF DISEASE EVOLUTION FROM HEALTHY TO MM. IN SPECIFIC AIM 1, WE WILL MAP THE SPATIAL INTERACTIONS AMONG EARLY B CELL CLONAL EXPANSIONS WITH THE MICROENVIRONMENT USING XENIUM SPATIAL TRANSCRIPTOMIC AND IMAGING MASS CYTOMETRY (IMC). IN SPECIFIC AIM 2, WE WILL CHART THE SUBCLONAL GENOMIC STRUCTURE AT THE SINGLE CELL LEVEL ACROSS THE SPECTRUM OF DISEASE FROM HEALTHY TO MM, AND IN SPECIFIC AIM 3, WE WILL CHARACTERIZE AT THE SINGLE CELL LEVEL THE MICROENVIRONMENT (IMMUNE AND NON-IMMUNE STROMAL CELLS) AND ITS ASSOCIATION WITH PROGRESSION ACROSS THE SPECTRUM OF DISEASE FROM HEALTHY TO MM. THIS PROVIDES A UNIQUE OPPORTUNITY TO STUDY EVENTS IN A CLINICALLY WELL-DEFINED PRECANCER HEMATOLOGICAL CONDITION THAT CAN BE A GREAT MODEL OF DISEASE PROGRESSION AND INFORM OTHER PRECANCER CELL ATLASES. WE ALSO HAVE ACCESS TO SERIAL BLOOD AND MARROW SAMPLES ALONG THE SPECTRUM OF THE DISEASE WITH LONG-TERM FOLLOW UP OF CLINICAL PROGRESSION FOR OVER 10 YEARS. UNLIKE IN SOLID CANCERS, WE CAN OBTAIN BIOPSIES FROM THE TISSUE OF ORIGIN WITHOUT ALTERING THE NATURAL COURSE OF THE PRECANCEROUS LESIONS (NO NEED FOR SURGICAL RESECTION) AND THEREFORE, WE HAVE A UNIQUE RESOURCE THAT CAN BE MADE AVAILABLE FOR OTHER PRECANCER ATLASES.

HUMAN MAB COCKTAILS TO PREVENT & TREAT H5N1 AVIAN INFLUENZA

AVON-NCI PFP PROGRAM: PREDICTING TREATMENT RESPONSE IN ER POSITIVE BREAT CANCER

MAPPING THE HUMAN BINARY INTERACTOME NETWORK

MAPPING THE FIRST HALF OF THE REFERENCE HUMAN BINARY PROTEIN INTERACTOME

BROAD SPECTRUM NEUTRALIZING HUMAN ABS TO SARS AND RELATED CORONAVIRUSES

CONTROL OF MITOCHONDRIAL BIOENERGETIC FUNCTION THROUGH THE MTOR PATHWAY

ANALYSIS OF INTESTINAL GENES REGULATED BY THE TRANSCRIPTION FACTOR CDX2

VALIDATION AND EXTENSION OF THE PREMM MODEL FOR MISMATCH REPAIR GENE MUTATIONS

RBPI21: DEVELOPMENT OF A NOVEL RADIATION MITIGATOR

RADIATION ONCOLOGY AT THE INTERFACE OF PEDIATRIC CANCER BIOLOGY AND DATA SCIENCE - PROJECT SUMMARY BASIC SCIENTISTS AND CLINICAL INVESTIGATORS FROM DANA-FARBER/HARVARD CANCER CENTER (DF/HCC) JOIN FORCES WITH THEIR COUNTERPARTS AT UNIVERSITY OF CALIFORNIA, SAN FRANCISCO’S (UCSF) HELEN DILLER FAMILY COMPREHENSIVE CANCER CENTER TO PROPOSE A HARVARD/UCSF ROBIN CENTER. OUR OBJECTIVE IS TO IMPROVE POTENCY AND SELECTIVITY OF TWO KEY RADIATION MODALITIES--EXTERNAL BEAM RADIATION AND RADIOPHARMACEUTICALS. A DISTINCTIVE FEATURE 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 OF THESE TWO PEDIATRIC CANCERS ARE FOUND ALSO IN MORE COMMON ADULT SOLID TUMORS. MOREOVER, THE LOW MUTATIONAL BURDEN OF THESE PEDIATRIC CANCERS PROVIDES A CLEAN GENETIC BACKGROUND FOR THE “LOW N/HIGH CONTENT” MOLECULAR CHARACTERIZATION TRIALS (MCTS) SPECIFIED BY THE ROBIN RFA. THE MALIGNANT CELLS WITHIN DMG AND NBL ARE HETEROGENOUS WITH RESPECT TO DEVELOPMENTAL STAGE. THE CENTRAL HYPOTHESIS OF OUR STUDY PLAN IS THAT THIS DEVELOPMENTAL HETEROGENEITY IS ECHOED AT THE LEVEL OF RADIATION-RESPONSE MECHANISMS AND ENABLES RADIATION RESISTANCE. 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 TREATED PROSPECTIVELY WITH A UNIFORM RADIOTHERAPY REGIMEN TO TEST THE PREDICTION THAT RADIATION SELECTS FOR RADIORESISTANT INTRA-TUMORAL VARIANTS. PROJECT 2 TESTS THE PREDICTION THAT 131I-MIBG THERAPY OF AGGRESSIVE NEUROBLASTOMA SELECTS FOR INTRA-TUMORAL SUBTYPES WITH UNFAVORABLE RESPONSES TO TREATMENT. OUR ROBIN MCT PROVIDES RESOURCES NEEDED TO COMPLETE THE OBJECTIVES AND SPECIFIC AIMS OF THE TWO PROJECTS. MULTIMODAL ANALYSIS AND MATHEMATICAL MODELING OF DATA FROM THE PROJECTS AND THE MCT WILL BE PERFORMED IN A CLINICAL ARTIFICIAL INTELLIGENCE 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 CENTER’S “OUTWARD FACE” TO THE BROADER SCIENTIFIC COMMUNITY AND LAY PUBLIC. THE CENTER WILL SERVE AS A “VALUE-ADDED” COMPONENT OF THE NCI’S EXTRAMURAL SUPPORT MISSION BY LEVERAGING (I) P30 CORE FACILITIES OF DF/HCC AND UCSF, (II) A U54-FUNDED DFCI PHYSICAL SCIENCES ONCOLOGY CENTER, AND (III) THE NCI'S EXPERIMENTAL THERAPEUTICS CLINICAL TRIALS NETWORK AND NATIONAL CLINICAL TRIALS NETWORKS. CONVERSELY, AN NCI ROBIN AWARD TO THE HARVARD/UCSF CENTER WOULD BE “VALUE-ADDED” TO THE FIELD OF RADIATION ONCOLOGY BY CATALYZING PRODUCTIVE INTERACTIONS BETWEEN RADIATION BIOLOGY, ARTIFICIAL INTELLIGENCE, AND DATA SCIENCE – DISCIPLINES THAT ARE WELL-ESTABLISHED IN BOSTON AND SAN FRANCISCO BUT HAVE NEVER BEEN APPLIED COORDINATELY TO THE PROBLEM OF RADIORESISTANCE. CENTER CO-LEADS, PROFESSORS DAPHNE HAAS-KOGAN M.D. AND FRANZISKA MICHOR, PH.D. HAVE MUCH EXPERIENCE IN MANAGEMENT OF MULTI-INVESTIGATOR, MULTI-INSTITUTIONAL RESEARCH PROGRAMS TOGETHER WITH COMPLEMENTARY SKILLSETS IN RADIATION ONCOLOGY AND ADVANCED DATA SCIENCE.

INVESTIGATION OF A MULTICANCER EARLY DETECTION TEST IN A HIGH-RISK MILITARY POPULATION

REPROGRAMMING OF T CELLS FOR THE TREATMENT OF MELANOMA

NOVEL IMMUNOLOGIC DISCOVERY PLATFORMS TO PREVENT METASTASIS AND RECURRENCE IN BREAST CANCER

PROSPECTIVELY RANDOMIZED, PLACEBO-CONTROLLED PHASE 3 STUDY TO DETERMINE THE EFFECT OF DENOSUMAB ON BREAST CANCER PREVENTION IN BRCA1 MUTATION CARRIERS

CONTROL OF PGC1ALPHA TRANSLATION AND FUNCTION

MECHANISM AND FUNCTION OF AUTOSOMAL ANALOG OF X INACTIVATION

SYSTEMS ANALYSIS OF CANCER PATHWAYS IN MOUSE MODELS

PGC-1 AND THE CONTROL OF HEPATIC GLUCONEOGENESIS

FUNCTIONAL GENOMIC ANALYSIS OF THE CD8 T CELL RESPONSE TO HIV VACCINES IN

CONVERGENT EPIGENETIC CONTROL OF NEUROENDOCRINE CANCERS - SUMMARY (OVERALL) THE OVERALL GOAL OF THE PROGRAM “CONVERGENT EPIGENETIC CONTROL OF DIVERSE NEUROENDOCRINE CANCERS” IS TO INTERROGATE EPIGENETIC AND TRANSCRIPTIONAL STATES THAT ARE REQUIRED FOR THE DEVELOPMENT OF NEUROENDOCRINE (NE) CANCERS. WE PROPOSE TO STUDY NE CANCERS IN FOUR TISSUE TYPES TO TEST THE HYPOTHESIS THAT THE NE PHENOTYPE IS DEPENDENT ON A COMMON SET OF TRANSCRIPTION FACTORS AND EPIGENETIC REGULATORS THAT CONTROL GENE EXPRESSION PATTERNS AND CREATES VULNERABILITIES THAT PROVIDE OPPORTUNITIES FOR THE IDENTIFICATION AND VALIDATION OF NEW TARGETS FOR THERAPEUTICS. TO ACCOMPLISH THIS GOAL, WE WILL STUDY SMALL INTESTINAL NEUROENDOCRINE TUMORS (SI-NET) TUMORS, NEUROENDOCRINE PROSTATE CANCER (NEPC), SMALL CELL LUNG CANCER (SCLC), AND CUTANEOUS MERKEL CELL CARCINOMA (MCC). WE PROPOSE THAT THE INTEGRATED STUDY OF THIS DIVERSE SET OF NE CANCERS WILL PROVIDE A DEEPER UNDERSTANDING OF THE MECHANISMS FOR NE TRANSFORMATION, INCLUDING THE PROPENSITY FOR LINEAGE PLASTICITY AS WELL AS THERAPEUTIC STRATEGIES TO IMPROVE RESPONSES TO TARGETED AND IMMUNE THERAPY. THE PROGRAM PROJECT HAS THREE PROJECTS PLUS AN EPIGENOMICS CORE UTILIZED BY ALL THREE PROJECTS AND IS COORDINATED BY AN ADMINISTRATIVE CORE. EACH PROJECT IS LED BY TWO CO-LEADERS THAT WILL FACILITATE INTERACTIONS ACROSS THE PROGRAM. EACH PROJECT AND CORE SPECIFIES A SPECIFIC AIM OF THE PROGRAM. PROJECT 1, “EPIGENETIC CONTROL OF NORMAL AND MALIGNANT NEUROENDOCRINE DIFFERENTIATION”, IS CO-LED BY RAMESH SHIVDASANI AND MYLES BROWN. PROJECT 1 AIMS TO DEFINE THE TRANSCRIPTIONAL AND EPIGENETIC BASIS OF HUMAN INTESTINAL NE DIFFERENTIATION AND THEN EXAMINE HOW THIS MOLECULAR UNDERSTANDING MIGHT INFORM THERAPEUTIC APPROACHES TOWARD CASTRATION-RESISTANT NEPC. PROJECT 2, “EPIGENETIC DRIVERS OF LINEAGE PLASTICITY IN LUNG CANCER” IS CO-LED BY MATTHEW OSER AND DAVID BARBIE. THROUGH STUDYING EED INACTIVATION IN SCLC IN IMMUNOCOMPETENT TUMOR MICROENVIRONMENT, WE WILL IDENTIFY THE EPIGENETIC MECHANISMS THAT PROMOTE HISTOLOGICAL LINEAGE PLASTICITY. PROJECT 3, “INSM1, A CANDIDATE THERAPEUTIC TARGET IN HIGH-GRADE NEUROENDOCRINE CARCINOMAS”, IS CO-LED BY JAMES DECAPRIO AND MATTHEW OSER. PROJECT 3 WILL DETERMINE IF INSM1 CAN SERVE AS THERAPEUTIC TARGET IN HIGH GRADE NE CARCINOMAS AND IDENTIFY IMIDS THAT DEGRADE INSM1. THE EPIGENOMICS CORE WILL PROVIDE BIOINFORMATIC ANALYSIS AND INTEGRATION OF THE DATA DERIVED FROM THE MOLECULAR PROFILING EXPERIMENTS PROPOSED. THE ADMINISTRATIVE CORE, LED BY JAMES DECAPRIO, WILL WORK TO ENSURE CONTINUED FOCUS ON DECIPHERING THE CONVERGENT EPIGENETIC CONTROL OF DIVERSE NEUROENDOCRINE CANCERS.

SPATIAL CONSIDERATIONS IN NEURONAL SURVIVAL SIGNALS

A RANDOMIZED PHASE 2 TRIAL EVALUATING THE NOVEL PI3KD INHIBITOR ROGINOLISIB WITH VENETOCLAX/RITUXIMAB FOR THE TREATMENT OF RELAPSED CLL PATIENTS

A HUMAN BINARY INTERACTOME REFERENCE MAP BY 2020

A MULTI-FACETED APPROACH TO IDENTIFYING K-RAS SYNTHETIC LETHAL RELATIONSHIPS

MOLECULAR PATHOGENESIS OF FANCONI ANEMIA

PRE-IND STUDIES OF FIRST-GENERATION DUAL-TARGETED, FINE-TUNED, IMMUNE-RESTORING (DFIR) CAR-T CELL THERAPY TO ACHIEVE CURES OF CLEAR CELL RENAL CELL CARCINOMA (CCRCC)

BRCA1 FUNCTION IN POST-DAMAGE NUCLEAR FOCI

DISCOVERY AND OPTIMIZATION OF NOVEL MUTANT-SELECTIVE ALLOSTERIC INHIBITORS OF EGFR T790M

GENERATION AND VALIDATION OF A COMPREHENSIVE HUMAN DISEASE MUTANT ORF RESOURCE

IMMUNE MODULATION/HEMATOPOIETIC CELL TRANSPLANTATION

TARGETING THE CYTOKINE CIRCUITRY OF KRAS-DRIVEN LUNG CANCER

INHIBITOR-SENSITIVE AND -RESISTANT EGFR MUTANTS FROM LUNG CANCER AND GLIOBLASTOMA

CYCLIN A FUNCTION IN NORMAL PROLIFERATION AND IN NEOPLASIA

NOVEL RANDOMIZED CONTROLLED TRIALS OF VITAMIN D SUPPLEMENTATION IN PATIENTS WITH COLORECTAL CANCER: IMPACT ON SURVIVAL AND BIOLOGY

PGC-1 AND NUCLEAR RECEPTORS IN ADAPTIVE THERMOGENESIS

PROMOTING RESILIENCE IN EARLY SURVIVORSHIP AMONG ADOLESCENTS AND YOUNG ADULTS WITH CANCER. - PROJECT SUMMARY ADOLESCENTS AND EARLY YOUNG ADULTS (AYAS, 12-25 YEARS-OLD) WITH CANCER ARE AT HIGH RISK OF POOR PSYCHOSOCIAL OUTCOMES BECAUSE THEIR DISTINCT DEVELOPMENTAL CHALLENGES ADD TO THE BURDEN OF CANCER. THIS IS PARTICULARLY TRUE WHEN AYAS TRANSITION FROM ACTIVE TREATMENT TO CANCER-SURVEILLANCE (“EARLY SURVIVORSHIP”) BECAUSE THIS TIME DEMANDS INCREASING AUTONOMY, RE-INTEGRATION INTO SOCIAL, EDUCATIONAL/VOCATIONAL NETWORKS, AND RE-EVALUATION OF SELF-IDENTITY. WE CREATED “PROMOTING RESILIENCE IN STRESS MANAGEMENT” (PRISM): A NOVEL, BRIEF, SKILLS-BASED PROGRAM PROMOTING AYA-ENDORSED “RESILIENCE RESOURCES” (STRESS-MANAGEMENT, GOAL-SETTING, POSITIVE-REFRAMING, AND MEANING-MAKING). PRISM INVOLVES 4, 30-60 MINUTE TELEHEALTH SESSIONS BETWEEN AYAS AND CERTIFIED PRISM COACHES, PLUS AN AWARD-WINNING SMARTPHONE APP. IN A PHASE 2 RANDOMIZED TRIAL OF 92 AYAS RECEIVING CANCER-TREATMENT, PRISM IMPROVED PATIENT-REPORTED RESILIENCE, QUALITY OF LIFE, HOPE, BENEFIT-FINDING, AND PSYCHOLOGICAL DISTRESS EARLY AFTER ITS DELIVERY, COMPARED TO USUAL CARE. WHILE THESE FINDINGS WERE PROMISING, THEY WERE TEMPERED BY 3 KEY THREATS TO PRISM’S SCALABILITY: (1) PRISM’S DELIVERY DEMANDS SCARCE HUMAN RESOURCES THAT MIGHT BE REPLACED BY DIGITAL MEDIA; (2) PRISM’S DURABILITY WAS LIMITED AFTER THE STUDY ENDED; AND, (3) WE LACKED TOOLS TO RECOGNIZE REAL-TIME CHANGES IN AYA DISTRESS THAT WARRANTED ADDITIONAL SUPPORT. THUS, WE NOW PROPOSE A MULTI-CENTER, SEQUENTIAL, MULTIPLE ASSIGNMENT, RANDOMIZED TRIAL (SMART) TO ADDRESS THESE 3 BARRIERS AMONG AYA SURVIVORS OF CANCER. SPECIFICALLY, WE AIM TO: (1) EVALUATE THE EFFICACY OF VIDEO- AND TEXT-PRISM COACHING VS. THE SELF-GUIDED MPRISM APP; (2) DETERMINE THE OPTIMAL METHOD FOR MAINTENANCE OF PRISM-RESPONSE; AND (3) EXPLORE CORRELATIONS BETWEEN PATIENT-REPORTED RESILIENCE, DISTRESS, HOPE, QUALITY OF LIFE, ANXIETY, AND DEPRESSION WITH VALIDATED INSTRUMENTS AND: (A) IN-APP RESILIENCE AND STRESS RATINGS, AND (B) DIGITAL PHENOTYPE (PASSIVE SMART-PHONE DATA INCLUDING PHONE/TEXT LOGS AND ACCELEROMETER DATA). WITH SMART DESIGN, N=325 ENGLISH OR SPANISH SPEAKING AYAS FROM 3 DIVERSE U.S. REGIONS (NORTHWEST/ALASKA/HAWAII, MIDWEST, AND SOUTH) WHO COMPLETED CANCER-DIRECTED THERAPY WITHIN THE PAST 2 YEARS WILL BE RANDOMIZED 1:2:2 FIRST TO RECEIVE APP-ONLY, VIDEO, OR TEXT-BASED PRISM LAY-COACHING. RESPONDERS IN THE VIDEO- AND TEXT- ARMS WILL BE RANDOMIZED 1:1 SECOND TO APP-ONLY (LOW) MAINTENANCE OR TEXT- BASED (HIGH) MAINTENANCE. BECAUSE NON-RESPONSE SUGGESTS A DEMAND FOR MORE IN-PERSON ENGAGEMENT, TEXT NON-RESPONDERS WILL BE NON-RANDOMLY ASSIGNED TO VIDEO, AND VIDEO NON-RESPONDERS WILL RECEIVE REFERRALS TO SPECIALTY CARE. EXPLORATORY ANALYSES WILL EVALUATE THE ROLE OF IN-APP AND DIGITAL PHENOTYPIC DATA IN DETECTING REAL-TIME AYA DISTRESS. THIS PROPOSAL IS SIGNIFICANT BECAUSE EARLY SURVIVORSHIP IS HIGHLY STRESSFUL FOR AYAS WITH CANCER, AND WE PROPOSE A SCALABLE, EVIDENCE-BASED PROGRAM TO SUPPORT AYA RESILIENCE. FINDINGS WILL FACILITATE AN ACCESSIBLE, SUSTAINABLE, EVIDENCE-BASED PROGRAM DESIGNED TO TARGET AND MEET THE NEEDS OF THOUSANDS OF AYAS, IN TURN ALLEVIATING THE BURDENS OF CANCER SURVIVORSHIP AND IMPROVING THEIR QUALITY OF LIFE.

THE ROLE OF CLONAL HEMATOPOIESIS IN THE DEVELOPMENT AND THERAPY OF MYELOID MALIGNANCIES

ENGINEERING EPIGENETIC THERAPY FOR SICKLE CELL DISEASE

IBCSG STATISTICAL CENTER--A BREAST CANCER STUDY RESOURCE

DEFINING MECHANISMS OF SUCCINATE REGULATION OVER ADIPOSE TISSUE THERMOGENESIS

SYSTEMS BIOLOGY OF IMMUNE RECONSTITUTION IN HIV / AIDS

MOLECULAR AND IMMUNE DRIVERS OF IMMUNOTHERAPY RESPONSIVENESS IN PROSTATE CANCER

TARGETING TO EPIGENETIC MODICATIONS IN ALL

REGULATION OF BROWN FAT: TOWARD NEW THERAPY FOR HUMAN OBESITY

OPTIMIZED B7-H3 CAR T CELLS FOR CHILDREN AND YOUNG ADULTS WITH SARCOMAS AND OTHER B7-H3+ SOLID TUMORS

DEFINING MECHANISMS OF IMMUNOTHERAPY RESISTANCE IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS

THERAPEUTIC TARGETING OF IMMUNE EVASION FROM THE MICA - NKG2D PATHWAY

ENHANCED RADIOTHERAPY FOR PEDIATRIC GLIOMA VIA SYNTHETIC LETHAL VULNERABILITIES - PROJECT SUMMARY DIFFUSE MIDLINE GLIOMAS (DMG) ARE THE MOST COMMON MALIGNANT BRAIN TUMORS OF CHILDREN. THEY ARE SURGICALLY INACCESSIBLE AND REFRACTIVE TO CHEMOTHERAPY. THE PREVALENT ONCOGENIC DRIVER--AN H3K27M MUTATION OF HISTONE H3--IS UNDRUGGABLE. RADIOTHERAPY IS THE STANDARD OF CARE FOR DMG, AND THE ONLY TREATMENT THAT PROLONGS PATIENT SURVIVAL. HOWEVER, H3K27M DMGS INEVITABLY RECUR FOLLOWING RADIOTHERAPY AND ARE UNIFORMLY FATAL. AGAINST THIS BACKDROP, WE PROPOSE THIS R01 RESPONSE TO PAR-22-198 FROM THE NCI ENTITLED “PRECISION APPROACHES IN RADIATION SYNTHETIC COMBINATIONS (PAIRS).” OUR BROAD GOAL IS TO IMPROVE SURVIVAL OF CHILDREN WITH DMG. THE POINT OF DEPARTURE FOR OUR STUDY PLAN IS A RECENTLY COMPLETED GENOME-WIDE CRISPR SCREEN AIMED AT IDENTIFYING DMG-SPECIFIC VULNERABILITIES. OUR SCREEN IDENTIFIED A CONDITIONAL SYNTHETIC LETHALITY AT THE JUNCTION OF REPLICATION STRESS (RS) AND THE CONSEQUENT DNA DAMAGE RESPONSE (DDR). THIS VULNERABILITY IS DRUGGABLE AND HAS POTENTIAL TO ENHANCE THE EFFICACY OF RADIOTHERAPY IN DMG SYNERGISTICALLY--A STRATEGY SPECIFICALLY PROPOSED BY PAIRS. OUR TESTABLE HYPOTHESIS IS THAT A SUSTAINABLE BALANCE BETWEEN RS AND DDR IN DMGS CAN BE TIPPED TO THERAPEUTIC ADVANTAGE BY COMBINING RADIATION AND ATR ANTAGONISTS (WHICH INCREASE RS) OR BY RADIATION PLUS INHIBITORS OF DNA POLYMERASE Q (WHICH DECREASE DDR). IN COLLABORATION WITH A CORPORATE PARTNER, WE HAVE IDENTIFIED CLINICAL-STAGE, BRAIN-PENETRANT ANTAGONISTS OF ATR AND POLQ. FOR CLINICAL TRIALS WE ARE AN INTEGRAL MEMBER OF THE INTERNATIONAL PACIFIC PEDIATRIC NEURO- ONCOLOGY CONSORTIUM (PNOC). DRAWING UPON THESE RESOURCES, OUR AIMS ARE TO TEST THREE SPECIFIC PREDICTIONS OF OUR HYPOTHESIS. AIM 1 (TARGET SPECIFICITY) TESTS THE PREDICTION THAT SYNERGISTIC KILLING OF DMG CELLS BY THE COMBINATION OF RADIATION PLUS ATR OR POLQ ANTAGONIST REFLECTS “ON TARGET” RESPONSES TO ENHANCED RS OR SUPPRESSED DDR (INDUCED BY ATR OR POLQ ANTAGONIST, RESPECTIVELY). AIM 2 (CHROMATIN STRUCTURE) TESTS THE PREDICTION THAT THE H3K27M DRIVEN ALTERED CHROMATIN PROPELS DEPENDENCY ON ATR AND POLQ. AIM 3 (THERAPEUTIC POTENTIAL) TESTS THE PREDICTIONS THAT (A) THE VARIABILITY IN DMG PATIENT RESPONSES TO RADIOTHERAPY REFLECTS PATIENT-SPECIFIC DIFFERENCES IN THE PRE-THERAPEUTIC BURDEN OF DDR AND RS AND (B) THAT MARKERS OF RS AND DDR WILL CORRELATE WITH RESPONSE TO THERAPY IN “AVATAR CLINICAL TRIALS” WITH PATIENT-DERIVED XENOGRAFTS OF DMGS. THE STUDY PLAN IS ENABLED BY AN INTERACTIVE COLLABORATION AMONG THREE INVESTIGATORS WHOSE SKILL SETS EXCEED THE SUM OF THEIR PARTS. DAPHNE HAAS-KOGAN, M.D. IS A CLINICIAN-SCIENTIST WITH MUCH PRACTICAL EXPERIENCE IN THE CLINICAL CARE OF CHILDREN WITH DMG. AS CHAIR OF RADIATION ONCOLOGY AT DANA-FARBER CANCER INSTITUTE, DHK INTERACTS FREQUENTLY WITH DIPANJAN CHOWDHURY, PH.D. - A DNA ENZYMOLOGIST WITH DEEP EXPERTISE IN DNA REPLICATION AND REPAIR. IN CLINICAL STUDIES PROPOSED FOR AIM 3, DHK AND DC WILL WORK CLOSELY WITH SABINE MUELLER, M.D. - AN EXPERT ON THE DESIGN AND CONDUCT OF CLINICAL TRIALS AND LEADER OF THE PNOC CONSORTIUM.

CHROMATIN AND TRANSCRIPTIONAL CONTROL OF LGR5+ CRYPT BASE STEM CELLS

MUC1-C IS A TARGET FOR REVERSING IMMUNE EVASION AND RESISTANCE TO IMMUNOTHERAPIES

MOLECULAR MECHANISMS UNDERLYING LINEAGE PLASTICITY IN PROSTATE CANCER

TUMOR CELL BIOLOGY TRAINING PROGRAM

DATA ANALYSIS TOOLS FOR EMERGING HIGH-THROUGHPUT TECHNOLOGIES

MOLECULAR PREDICTION OF MYELOMA INITIATION MOLECULAR PREDICTION OF MYELOMA INITIATION - SUMMARY MULTIPLE MYELOMA (MM) IS THE SECOND MOST COMMON HEMATOLOGIC MALIGNANCY AND IS ALMOST ALWAYS PRECEDED BY MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) AND SMOLDERING MYELOMA (SMM). RECENT RANDOMIZED 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 MM OCCURS MAY LEAD TO IMPROVED SURVIVAL AND DECREASED MORBIDITY FROM OTHER COMPLICATIONS SUCH AS BONE FRACTURES, RENAL FAILURE AND HOSPITALIZATIONS RELATED TO END-ORGAN DAMAGE FROM MYELOMA. EARLY DETECTION REQUIRES A COMPREHENSIVE SCREENING OF THE POPULATION AT RISK FOR DEVELOPING MM. KNOWN RISK FACTORS FOR DEVELOPING MM INCLUDE AGING, RACE (BLACKS), AND FAMILIAL HISTORY OF HEMATOLOGIC MALIGNANCIES. OUR PRELIMINARY DATA OF SCREENING ~7,500 ETHNICALLY DIVERSE INDIVIDUALS AT RISK OF DEVELOPING MM USING A SENSITIVE QUANTITATIVE MALDI-TOF MASS SPECTROMETRY HAS SHOWN A PREVALENCE RATE OF MONOCLONAL PROTEIN IN 45% IN INDIVIDUALS OF AGE >50Y AND HAVING AN EARLY IMMUNE DYSREGULATION THAT WE TERMED MONOCLONAL GAMMOPATHY OF INDETERMINATE POTENTIAL (MGIP). MGUS WAS SIGNIFICANTLY MORE PREVALENT IN BLACK PARTICIPANTS AND PARTICIPANTS WITH FAMILIAL HEMATOLOGIC MALIGNANCY (HM) HISTORY THAN IN WHITE PARTICIPANTS WITH NO FAMILY HISTORY OF HM. TO BEGIN TO DELINEATE MECHANISMS BY WHICH THESE EARLY MGIP CLONES PROGRESS TO MGUS AND FURTHER LEAD TO MM, WE PLAN TO EXPLORE THE HOST INTRINSIC (AGE, RACE, GERMLINE RISK FACTORS) AND ACQUIRED (INFLAMMATION, ANTIGENIC ACTIVATION) RISK FACTORS ON THE EXPANDING CLONE AND ITS ENVIRONMENT THAT INFLUENCE ITS BEHAVIOR. WE BELIEVE THE NEXT FRONTIER IN MM RESEARCH 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 APPROACHES TO TREATMENT AND SERVE AS A PARAGON OF CANCER PREVENTION. WE HYPOTHESIZE THAT DEFINING RISK AS ANCESTRY SCORES AND GENOMIC SIGNATURES, INSTEAD OF DEFINING RISK BY SELF-IDENTIFIED RACE, CAN IMPROVE RISK PREDICTION FOR MM. SIMILARLY, INSTEAD OF USING CHRONOLOGICAL AGE AS A RISK FACTOR FOR MM, WE WILL TEST THE HYPOTHESIS 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 CARCINOGENIC PROCESS LINKED TO MM. THIS APPROACH WILL ALLOW THE FIELD TO TRANSITION FROM A PURELY DEMOGRAPHIC DEFINITION OF RISK TO A BIOLOGICAL ONE.

THE ALK RECEPTOR TYROSINE KINASE AS A THERAPEUTIC TARGET IN NEUROBLASTOMA

IDENTIFICATION OF NOVEL PROTEIN KINASES DEPENDENT ON PHOSPHOCREATINE RATHER THAN ATP

STROMAL MODULATION OF PANCREATIC CANCER MALIGNANT CELL STATE AND THERAPEUTIC SENSITIVITY - ABSTRACT UNLIKE MANY CANCERS, PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS CHARACTERIZED BY A HYPOXIC, NUTRIENT- DEPRIVED, IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT (TME) AND A FIBROTIC STROMA THAT MAY IMPAIR TREATMENT RESPONSE. RECENT SINGLE-CELL STUDIES SUGGEST A COMPLEX INTERPLAY BETWEEN MALIGNANT TUMOR CELLS AND OTHER CELL TYPES WITHIN THE TME, WITH CROSSTALK BETWEEN TUMOR AND STROMAL CELL TYPES INFLUENCING MALIGNANT CELL PHENOTYPES, INCLUDING RESPONSES TO THERAPY. UNDERSTANDING THESE INTERACTIONS WILL PROVIDE INSIGHT INTO PDAC PROGRESSION AND THERAPY RESISTANCE. IN PARTICULAR, CANCER-ASSOCIATED FIBROBLASTS (CAFS) ARE A MAJOR NON-IMMUNE CELL COMPONENT OF THE TME AND ARE COMPRISED OF SEVERAL DISTINCT SUBTYPES THAT VARY BASED ON TUMOR SUBTYPE AND THE SURROUNDING MICROENVIRONMENTAL NICHE. IN THIS PROPOSAL, WE BRING TOGETHER A MULTIDISCIPLINARY TEAM OF BASIC AND TRANSLATIONAL INVESTIGATORS THAT WILL BUILD UPON OUR PRIOR STUDIES TO INVESTIGATE THE TUMOR-TME CO-ORGANIZER MODEL WITH A FOCUS ON INTERROGATING INTERACTIONS BETWEEN PDAC TUMOR CELLS AND CAFS IN THE TME. SPECIFICALLY, WE WILL EXAMINE THE OVERARCHING HYPOTHESIS THAT RECIPROCAL SIGNALING BETWEEN TUMOR CELLS AND CAFS SHAPES MALIGNANT CELL AND CAF PHENOTYPES 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 SERIAL BIOPSIES TO STUDY THE PDAC TME CONTINUUM IN DISEASE PROGRESSION AND RESISTANCE TO THERAPY. SPECIFICALLY, WE PROPOSE (1) TO DETERMINE WHETHER TARGETING ORGAN-SPECIFIC PDAC-CAF INTERACTIONS ENHANCES THERAPEUTIC RESPONSES, (2) TO INTERROGATE NOVEL VULNERABILITIES RESULTING FROM TUMOR CELL AND CAF REPROGRAMMING DURING PDAC THERAPY, AND (3) INVESTIGATE WHETHER TGFB BLOCKADE DISRUPTS TUMOR CELL-CAF CROSSTALK AND SENSITIZES PDAC TO CHEMOTHERAPY. IN PURSUING THESE STUDIES, WE WILL WORK WITH OTHER MEMBERS OF THE PDAC STROMAL REPROGRAMMING CONSORTIUM (PSRC) TO PURSUE COLLABORATIVE STUDIES TO UNDERSTAND HOW PDAC AND TME INTERACTIONS PROGRAM TUMOR PROGRESSION AND THERAPY RESPONSES.

CENTERS FOR MEDICAL COUNTERMEASURES AGAINST RADIATION

REWIRING OF REGULATORY NETWORKS IN BREAST CANCER BY TRANSCRIPTION FACTOR ISOFORMS

STUDIES OF IGHV GERMLINE GENE POLYMORPHISM, UTILIZATION & SHIFTING FOR SEASONAL INFLUENZA VACCINE INDUCED BROADLY NEUTRALIZING ANTIBODY RESPONSES

BUILDING CER CAPACITY: ALIGNING CRN, CMS, AND STATE RESOURCES TO MAP CANCER CARE

COMPLEMENTARY SIGNALING PATHWAYS IN HODGKIN LYMPHOMA AND RELATED MALIGNANCIES

PREPROCESSING AND ANALYSIS TOOLS FOR CONTEMPORARY MICROARRAY APPLICATIONS

THE MOLECULAR BASIS OF IMID INDUCED NEO-SUBSTRATE RECRUITMENT TO THE CRL4CRBN UBIQUITIN E3 LIGASE.

END-OF-LIFE CARE FOR ADOLESCENTS AND YOUNG ADULTS WITH CANCER: AN EVALUATION OF CARE AND DEVELOPMENT OF PATIENT-CENTERED QUALITY MEASURES

CONTROL OF ADIPOCYTE GENE EXPRESSION AND PHYSIOLOGY

ACUPUNCTURE FOR CHEMOTHRAPY-INDUCED PERIPHERAL NEUROPATHY TREATMENT (ACT)TRIAL - PROJECT SUMMARY ONE OF THE MOST HARMFUL SIDE EFFECTS OF CHEMOTHERAPY IS CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY (CIPN), A COMMON, PAINFUL, AND DISABLING SIDE EFFECT OF MANY CHEMOTHERAPY AGENTS FOR WHICH THERE IS NO EFFECTIVE TREATMENT. OUR PILOT PHASE IIB THREE-ARM TRIAL SHOWED THAT ACUPUNCTURE TREATMENT IS ASSOCIATED WITH REDUCED CIPN PAIN AND IMPROVED TACTILE THRESHOLD COMPARED TO PLACEBO AND USUAL CARE CONTROL. WE AIM TO INCREASE CANCER PATIENTS' FUNCTION AND QUALITY OF LIFE BY IDENTIFYING EFFECTIVE TREATMENTS TO ALLEVIATE CHEMOTHERAPY-RELATED TOXICITIES. THE GOAL OF THE PROPOSED PROJECT IS TO DETERMINE THE EFFICACY OF ACUPUNCTURE IN TREATING CIPN PAIN AND IMPROVING FUNCTION, AS WELL AS TO IMPROVE SENSORY NERVE RECOVERY IN CANCER SURVIVORS SUFFERING FROM MODERATE TO SEVERE CIPN PAIN. WE WILL CONDUCT A PHASE III, 250-PATIENT, RANDOMIZED, PLACEBO (SHAM ACUPUNCTURE)-CONTROLLED TRIAL TO: 1) DETERMINE THE EFFICACY OF AN EIGHT-WEEK EA TREATMENT ON CIPN SYMPTOMS AMONG CANCER SURVIVORS WITH MODERATE TO SEVERE CIPN PAIN; 2) EVALUATE THE EFFECT OF EA VS. SA ON SMALL SENSORY FIBER FUNCTION; AND 3) EVALUATE WHETHER BASELINE QST OUTCOMES PREDICT RESPONSE TO EA.

INSULIN SIGNALING AND METABOLIC EFFECTS THROUGH CLK2 KINASE

DISSECTING NEOEPITOPE-SPECIFIC CLONAL T CELL POPULATIONS IN ADVANCED MELANOMA PATIENTS VACCINATED WITH PERSONAL NEOANTIGEN PEPTIDES PARTNERED WITH LOCAL AND SYSTEMIC IMMUNE CHECKPOINT INHIBITION

IMPACT OF MHC GENOTYPE ON EX VIVO T CELL FUNCTION IN TYPE 1 DIABETES

INVESTIGATE ROLE OF MICRORNA CLUSTER 183-96-182 IN DNA REPAIR AND RADIOSENSITIVIT

BIOLOGICAL AND IMMUNOLOGICAL INFECTIOUS DISEASE AGENT AND CANCER VACCINE RESEARCH

METABOLIC VULNERABILITIES IN MELANOMA TUMORS

DISSECTING CCL5 CONTRIBUTION TO ANTIGEN SPECIFIC T CELL RESPONSES IN HEAD AND NECK CANCERS - PROJECT SUMMARY CORRELATIVE STUDIES OF IMMUNE CHECKPOINT BLOCKADE (ICB) SHOW THAT RESPONSE IS HIGHLY DEPENDENT ON THE QUANTITATIVE AND QUALITATIVE STATUS OF PRE-EXISTING ANTITUMOR T CELL CLONES. OF PARTICULAR IMPORTANCE IS THE RESERVOIR OF TISSUE RESIDENT MEMORY (TRM) T CELLS THAT POSITIVELY CORRELATE WITH RESPONSE TO ICB THERAPIES. OUR WORK IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCCS) LEADS US TO HYPOTHESIZE THAT TRM T CELLS ARE MAJOR PLAYERS IN THE EARLY ANTI-TUMOR IMMUNE RESPONSE TO IMMUNOTHERAPY AND THAT IDENTIFYING SPECIFIC CHEMOKINE AND CYTOKINE NETWORKS SHAPING THE DEVELOPMENT AND FUNCTIONALITY OF ANTITUMOR TRM CELLS WILL LEAD TO IMPROVED THERAPEUTIC STRATEGIES. USING SCRNASEQ AND SCTCRSEQ OF BASELINE AND ON TREATMENT TUMOR SAMPLES FROM A NOVEL NEOADJUVANT ANTI-PD1 HNSCC CLINICAL TRIAL (NCT02296684), WE DEMONSTRATED THAT RESPONDING TUMORS HAD CLONALLY EXPANDED PUTATIVE TUMOR SPECIFIC EXHAUSTED CD8+ TILS WITH A TRM PROGRAM, CHARACTERIZED BY HIGH CYTOTOXIC POTENTIAL AND ZNF683 EXPRESSION. BY CONTRAST, THE NON-RESPONDER BASELINE TUMOR MICROENVIRONMENT (TME) EXHIBITED RELATIVE ABSENCE OF CYTOTOXIC ZNF683+ TILS AND ACCUMULATION OF HIGHLY EXHAUSTED CLONES. TO DEFINE THE DETERMINANTS OF TRM-DEVELOPMENT, WE PURSUED MECHANISTIC STUDIES USING ANTI-PD1 RESPONSIVE OR RESISTANT HNSCC CELL LINE SYNGENEIC MOUSE MODELS. THIS WORK CONFIRMED THAT ANTITUMOR TRM-CELL ACTIVITY WAS POSITIVELY CORRELATED WITH INCREASED FREQUENCY AND FUNCTIONALITY OF TYPE 1 CONVENTIONAL DENDRITIC CELLS (CDC1) AND WITH ENHANCED CCL5 CHEMOKINE EXPRESSION IN BOTH HUMAN HNSCCS AND MOUSE MODELS. TO EXPAND OUR UNDERSTANDING OF TME AND TUMOR DRAINING LYMPH NODE SPECIFIC CCL5 DEPENDENT MECHANISMS UNDERLYING PRODUCTIVE OR INEFFECTIVE T CELL RESPONSES AGAINST HNSCC, WE WILL DISSECT CCL5 DRIVEN REMODELING OF THE TME INCLUDING DEFINING CELLULAR SOURCES AND ITS TARGET(S). WE WILL EXTEND THESE STUDIES TO HUMAN HNSCCS TO DISSECT CCL5 AND CCR5 CONTRIBUTIONS TO DC:T CELL INTERACTIONS IN FRESH TUMOR EXPLANTS. FINALLY, WE WILL USE A THERAPEUTIC APPROACH WITH A NOVEL ONCOLYTIC VIRUS TARGETED TO EPIDERMAL GROWTH FACTOR EXPRESSING TUMOR CELLS THAT ANCHORS CCL5 IN THE TME. TOGETHER, THIS WORK WILL ADDRESS THE KNOWLEDGE GAP REGARDING THE FACTORS UNDERLYING CYTOTOXIC VERSUS DYSFUNCTIONAL ANTITUMOR TUMOR INFILTRATING LYMPHOCYTES IN THE HNSCC TME.

A WEB-BASED PATIENT-REPORTED SYMPTOM MONITORING AND SELF-MANAGEMENT PORTAL FOR ADOLESCENT AND YOUNG ADULT BREAST CANCER SURVIVORS

MANIPULATION OF IMMUNE RESPONSIVENESS AFTER HEMATOPOIETIC CELL TRANSPLANTATION

INNATE CYTOKINE RESPONSES THAT REGULATE AUTOIMMUNITY

ADVANCED COMPUTATIONAL METHODS IN ANALYZING HIGH-THROUGHPUT SEQUENCING DATA

DEVELOPING INFORMATICS TECHNOLOGIES TO MODEL CANCER GENE REGULATION

GENETIC CONTROL OF NOCICEPTIVE SENSORY NEURON DEVELOPMENT AND PAIN BEHAVIOR

METABOLIC SYNDROME FATTY ACID SYNTHESIS AND PROSTATE CANCER

YOGA FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY TREATMENT (YCT) TRIAL - PROJECT SUMMARY CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY (CIPN) IS ONE OF THE MOST HARMFUL, COMMON, PAINFUL, AND DISABLING SIDE EFFECTS OF MANY CHEMOTHERAPY AGENTS AND THERE IS NO EFFECTIVE TREATMENT FOR IT. OUR PILOT PHASE IIB TWO-ARM TRIAL SHOWED THAT YOGA TREATMENT IS ASSOCIATED WITH REDUCED CIPN PAIN AND REDUCED RISK OF FALLS COMPARED TO USUAL CARE CONTROL. WE AIM TO INCREASE CANCER PATIENTS’ FUNCTION AND QUALITY OF LIFE BY IDENTIFYING EFFECTIVE TREATMENTS TO ALLEVIATE CHEMOTHERAPY-RELATED TOXICITIES. THE GOAL OF THE PROPOSED PROJECT IS TO DETERMINE THE EFFICACY OF YOGA IN TREATING CIPN PAIN AND IMPROVING FUNCTION, AS WELL AS TO IMPROVE SENSORY NERVE RECOVERY AND REDUCE THE RISK OF FALLS IN CANCER SURVIVORS SUFFERING FROM MODERATE TO SEVERE CIPN PAIN. WE WILL CONDUCT A PHASE III, RANDOMIZED, EDUCATION AND USUAL CARE- CONTROLLED TRIAL WITH 268 PARTICIPANTS TO: 1) DETERMINE THE EFFICACY OF AN EIGHT-WEEK YOGA TREATMENT ON CIPN SYMPTOMS AMONG CANCER SURVIVORS WITH MODERATE TO SEVERE CIPN PAIN; 2) EVALUATE THE EFFECT OF YOGA VERSUS EDUCATION CONTROL AND USUAL CARE ON IMPROVING FLEXIBILITY AND REDUCING THE RISK OF FALLS; AND 3) EVALUATE THE EFFECT OF YOGA VERSUS EDUCATION CONTROL AND USUAL CARE ON QUALITY OF LIFE AND SENSORY FIBER FUNCTIONING.

ANALYSIS TOOLS AND SOFTWARE FOR SECOND GENERATION SEQUENCING DATA

PRECISION ASSESSMENT AND DELIVERY OF CANCER RISKS IN BRCA 1/2 MUTATION CANCERS

TISSUE-BASED BIOMARKERS OF ANTI-PD-1-BASED THERAPY IN METASTATIC RENAL CELL CARCINOMA - PROJECT SUMMARY IMMUNOTHERAPY, PARTICULARLY IMMUNE CHECKPOINT INHIBITORS (ICI), HAS SHOWN CONSIDERABLE SUCCESS IN THE TREATMENT OF ADVANCED RENAL CELL CARCINOMA (RCC), LEADING TO DURABLE RESPONSES IN A SUBSET OF PATIENTS. HOWEVER, MOST PATIENTS DO NOT DERIVE LONG-TERM CLINICAL BENEFIT FROM EXISTING IMMUNE THERAPIES. MOVING FORWARD, OUR TEAM HAS PRIORITIZED IDENTIFYING THE DETERMINANTS OF ICI RESPONSE IN RCC, INCLUDING THE ANTIGENIC TARGETS, T CELL PHENOTYPES, AND MICROENVIRONMENT FEATURES THAT ULTIMATELY DICTATE THE EFFECTIVENESS OF TUMOR- SPECIFIC IMMUNITY. HUMAN ENDOGENOUS RETROVIRUSES (ERVS) ARE OFTEN ABERRANTLY EXPRESSED IN NUMEROUS DISEASE STATES, INCLUDING MALIGNANCY, AND CAN LEAD TO ACTIVATION OF BOTH INNATE IMMUNITY (THROUGH SENSING BY THE RIG-I/MDA-5 AND CGAS-STING PATHWAYS) AND ADAPTIVE IMMUNITY (BY PROVIDING ANTIGENIC TARGETS FOR TUMOR-SPECIFIC CD8+ T CELLS). THE EXPRESSION OF ERVE-4 HAS BEEN ASSOCIATED WITH RESPONSE TO ICI MONOTHERAPY (I.E. ANTI-PD-1) IN AN ANALYSIS OF A PHASE III RANDOMIZED CONTROLLED TRIAL IN RCC, AND AN ERV-DERIVED PEPTIDE (FROM ERVE-4) WAS IDENTIFIED AS A TARGET EPITOPE IN A LONG-TERM RCC RESPONDER TO ALLOGENEIC STEM CELL TRANSPLANT. BEYOND RECOGNITION OF TUMOR ANTIGENS, EFFECTIVE ANTI-TUMOR IMMUNITY REQUIRES A TUMOR MICROENVIRONMENT THAT PERMITS INFILTRATING CD8+ T CELLS TO CARRY OUT THEIR EFFECTOR FUNCTION. A HIGH LEVEL OF TUMOR INFILTRATION BY ANTIGEN- EXPERIENCED, NON-EXHAUSTED CD8+ T CELLS HAS BEEN ASSOCIATED WITH IMPROVED RESPONSE TO ICI MONOTHERAPY IN CLINICAL TRIALS OF RCC. HOWEVER, RESISTANCE TO ICI MONOTHERAPY IS STILL COMMON, IN PART OWING TO THE IMMUNOSUPPRESSIVE EFFECTS OF INFILTRATING TREG AND MYELOID CELLS, AND CONSEQUENTLY COMBINATION (AND NOT SINGLE AGENT) THERAPIES WITH PD-1 BLOCKADE AS A BACKBONE ARE NOW THE STANDARD-OF-CARE TREATMENT FOR ADVANCED RCC. IT IS THEREFORE CRITICAL TO UNDERSTAND THE ROLE OF ERV EXPRESSION, T CELL PHENOTYPE, AND THE IMMUNE MICROENVIRONMENT IN THE CONTEXT OF CLINICALLY RELEVANT CONTEMPORARY ICI-BASED COMBINATION THERAPIES. WE HYPOTHESIZE THAT ABERRANT EXPRESSION OF ERVS IS ASSOCIATED WITH IMPROVED RESPONSE TO ICI COMBINATION THERAPY WITH IPILIMUMAB AND NIVOLUMAB, AND THAT CHARACTERIZATION OF T CELL PHENOTYPES AND THE COMPOSITION AND STATES OF OTHER INFILTRATING IMMUNE CELLS IN THE RCC MICROENVIRONMENT WILL IMPROVE OUR UNDERSTANDING OF THE DETERMINANTS OF ICI RESPONSE. BY LEVERAGING OUR UNIQUE ACCESS TO CLINICALLY RELEVANT LARGE- SCALE CLINICAL TRIAL SPECIMENS OF SINGLE-AGENT ICI AND ICI-BASED COMBINATION THERAPY IN RCC, AS WELL AS OUR COLLABORATIVE TEAM OF PHYSICIANS, TRANSLATIONAL RESEARCHERS, AND EXPERIMENTAL BIOLOGISTS, WE AIM TO SYSTEMICALLY ASSESS THE ASSOCIATION OF ERV EXPRESSION AND ICI RESPONSE AND TO DETERMINE OTHER IMMUNE MICROENVIRONMENT FEATURES THAT ULTIMATELY INFLUENCE RESPONSE TO CURRENT RCC IMMUNOTHERAPIES. OUR MULTIDISCIPLINARY TEAM BRINGS TOGETHER A COLLECTIVE EXPERTISE IN RCC BIOLOGY, PATHOLOGY, AND TUMOR IMMUNOREGULATION WHO ARE DEDICATED TO BRINGING MEANINGFUL RESULTS THAT WILL OPTIMIZE CLINICAL OUTCOMES FOR PATIENTS WITH RCC.

POLYPLOIDY, ANEUPLOIDY, AND GENOME STABILITY

THE AYA-RISE INTERVENTION: RISK INFORMATION AND SCREENING EDUCATION FOR ADOLESCENTS AND YOUNG ADULTS WITH CANCER PREDISPOSITION SYNDROMES

(PQ8) GENETICALLY FAITHFUL MURINE MODELS FOR STUDYING DISEASE PROGRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA

REGULATION AND FUNCTION OF IKKE IN BREAST CANCER INITIATION AND MAINTENANCE

ADAPTING AND EVALUATING A BRIEF ADVICE TOBACCO INTERVENTION IN HIGH-REACH, LOW-RESOURCE SETTINGS IN INDIA

DRUG RESISTANCE IN LUNG CANCER

GENE TARGETS OF OLIG2 IN MALIGNANT GLIOMA STEM CELLS

MALT1 INHIBITORS FOR THE TREATMENT OF CHEMO-RESISTANT ABC-DLBCL

NEXT GENERATION COMPUTATIONAL TOOLS FOR FUNCTIONAL GENOMICS

MOLECULAR PREDICTION OF MYELOMA IN AFRICAN AMERICANS - SUMMARY MULTIPLE MYELOMA (MM) IS ALMOST ALWAYS PRECEDED BY EARLY PRECURSOR CONDITIONS: MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS) AND SMOLDERING MYELOMA (SMM). ABOUT 3% OF THE POPULATION >50 YEARS HAVE MGUS, MAKING IT A VERY COMMON PRECURSOR CONDITION. THE RISK IS 2-3 TIMES HIGHER IN PEOPLE WITH A FAMILY HISTORY OF MM OR WHO ARE BLACK/AFRICAN AMERICAN (AA). HERE, WE BELIEVE THAT INSTEAD OF DEFINING RISK BY RACE AND FAMILIAL HISTORY ONLY, WE WILL DEFINE RISK AS SPECIFIC GENOMIC SIGNATURES, SOME OF WHICH ARE RELATED TO RACE. BY SCREENING AT-RISK POPULATIONS FOR MGUS, ONE CAN DEVELOP EARLY PREVENTION AND INTERCEPTION STRATEGIES FOR PATIENTS WHO 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 PROMISE STUDY) THAT IS SCREENING 30,000 PARTICIPANTS AT-RISK OF DEVELOPING MM AND A LARGE RETROSPECTIVE TISSUE BANKING STUDY, THE MASS-GENERAL BRIGHAM (MGB) BIOBANK, WITH 123,000 SUBJECTS. HOWEVER, WHAT IS LACKING IS THE IDENTIFICATION OF BIOLOGICAL CANCER RISK MECHANISMS IN MM AND TRANSLATING THESE DISCOVERIES INTO CANCER INTERCEPTION AND EARLY THERAPEUTIC INTERVENTIONS. THIS APPROACH WILL ALLOW THE FIELD TO TRANSITION FROM A PURELY DEMOGRAPHIC DEFINITION OF RISK TO A BIOLOGICAL ONE. WE BELIEVE THAT SAMPLES FROM THE PLCO STUDY, ALONG WITH OUR CURRENT STUDY COHORTS, CAN HELP DEFINE THE MECHANISTIC UNDERPINNINGS OF THE CARCINOGENESIS PROCESS LEADING TO MGUS/MM. OUR OVERARCHING HYPOTHESIS IS THAT DEFINING THE RISK OF DEVELOPING MM PRECURSORS AT THE GENOMIC LEVEL CAN MORE PRECISELY IDENTIFY SPECIFIC POPULATIONS AT RISK THAN DEMOGRAPHIC ATTRIBUTES AND DEFINE FOCUSED STRATEGIES FOR EARLY INTERCEPTION. IN SPECIFIC AIM 1, WE DEFINE THE PREVALENCE OF MONOCLONAL GAMMOPATHIES IN HIGH-RISK PARTICIPANTS IN THE PLCO STUDY ALONG WITH MGB/PROMISE COHORTS AND CHARACTERIZE THEIR IMPACT ON LONG-TERM HEALTH OUTCOMES. IN SPECIFIC AIM 2, WE IDENTIFY GERMLINE VARIANTS THAT PREDISPOSE TO DEVELOPING MGUS/MM. WE AIM TO CHARACTERIZE THE GENETIC UNDERPINNINGS OF RISK RELATED TO RACE AND FAMILY HISTORY OF DISEASE. WE EXPECT THAT THIS APPROACH WILL ALLOW US TO MOVE PAST USING SELF-REPORTED RACE STATUS FOR RISK STRATIFICATION. IN SPECIFIC AIM 3, WE ASSESS THE ROLE OF IMMUNE AGING IN DEVELOPING MGUS/MM. MM IS TRADITIONALLY THOUGHT OF AS A DISEASE OF THE ELDERLY, BUT THE RISK MAY BE BETTER EXPLAINED BY THE "AGING TISSUE" OF ORIGIN RATHER THAN CHRONOLOGICAL AGE. THIS APPROACH WILL ALLOW US TO TRANSITION FROM A PURELY DEMOGRAPHIC DEFINITION OF RISK TO A BIOLOGICAL ONE.

(PQ3) A FUNCTIONAL GENOMIC APPROACH TO IDENTIFICATION AND INTERPRETATION OF GERMLINE-TUMOR GENETIC INTERACTIONS

CRLF2 SIGNALING IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

SYSTEMS BIOLOGY ANALYSIS OF HUMAN ERYTHROPOIESIS

STRUCTURE-ACTIVITY RELATIONSHIPS GOVERNING MAMMALIAN SWI/SNF CHROMATIN REMODELING ACTIVITY AS A FUNCTION OF CHROMATIN STATE - PROJECT SUMMARY RECENT WHOLE-EXOME SEQUENCING STUDIES IN HUMAN CANCER AND NEURODEVELOPMENTAL DISORDERS HAVE UNMASKED FREQUENT MUTATIONS IN GENES ENCODING CHROMATIN REGULATORY PROTEINS. SPECIFICALLY, GENES ENCODING SUBUNITS OF THE MAMMALIAN SWI/SNF ATP-DEPENDENT CHROMATIN REMODELING COMPLEXES (ALSO CALLED MSWI/SNF OR BAF COMPLEXES) ARE PERTURBED IN OVER 20% OF MALIGNANCIES, UNDERSCORING THEIR CRITICAL ROLES IN THE MAINTENANCE OF TIMELY AND APPROPRIATE GENE EXPRESSION. THE MECHANISMS BY WHICH MSWI/SNF FAMILY COMPLEXES ARE TARGETED ON CHROMATIN AND THE FEATURES OF THE HISTONE LANDSCAPE THAT GOVERN THEIR ACTIVITIES REMAIN UNKNOWN. INDEED, A SYSTEMATIC EVALUATION DEFINING THE CONTRIBUTIONS OF SPECIFIC HISTONE LANDSCAPE FEATURES TO CANONICAL BAF, PBAF, AND NON-CANONICAL BAF COMPLEX TARGETING AND ACTIVITY WOULD REPRESENT A SIGNIFICANT ADVANCEMENT IN THE FIELD AT- LARGE. HERE WE AIM TO: (1) DETERMINE THE GENOME-WIDE TARGETING OF DISTINCT, FINAL-FORM MSWI/SNF COMPLEXES IN HUMAN CELLS AND THE IMPACT OF SELECT CANCER-ASSOCIATED COMPLEX PERTURBATIONS; (2) DEFINE THE IN VITRO NUCLEOSOME REMODELING AND ATPASE ACTIVITIES OF ENDOGENOUSLY-PURIFIED MSWI/SNF SUBCOMPLEXES, BAF, PBAF, AND NCBAF, IN WILD-TYPE (WT) AND MUTANT STATES; AND (3) DETERMINE THE IMPACT OF CORE HISTONE VARIANTS AND HISTONE TAIL MODIFICATIONS ON MSWI/SNF COMPLEX NUCLEOSOME BINDING AND ACTIVITY. TAKEN TOGETHER, SUCCESSFUL COMPLETION OF THESE AIMS CENTERED AT THE INTERSECTION OF BIOCHEMISTRY, EPIGENETICS, AND CANCER BIOLOGY, WILL CONSTITUTE A HIGHLY TIMELY SERIES OF ADVANCES IN THE FIELD OF CHROMATIN BIOLOGY, AND WILL CONTRIBUTE IMPORTANT KNOWLEDGE REGARDING THE MECHANISM OF TARGETING OF MSWI/SNF COMPLEXES ACROSS A RANGE OF BOTH NORMAL AND ONCOGENIC STATES. GIVEN THAT A MAJOR IMPEDIMENT TO THE DEVELOPMENT OF ON-TARGET MODULATORY AGENTS OF MSWI/SNF COMPLEXES LIES IN THE LACK OF BIOLOGICAL UNDERSTANDING OF COMPLEX-SPECIFIC TARGETING AND FUNCTIONAL REGULATION, THE RESULTS OF THIS PROPOSAL ARE LIKELY TO PROVIDE THE BASIS FOR NEW APPROACHES TOWARD TARGETED DISRUPTION OF MSWI/SNF-CHROMATIN INTERACTIONS.