Institute For Cancer Research

CANCER CENTER SUPPORT GRANT

AI-DRIVEN STRUCTURE-ENABLED ANTIVIRAL PLATFORM (ASAP) - PROJECT SUMMARY/ABSTRACT - OVERALL SARS-COV-2 CONTINUES TO CAUSE SEVERE MORBIDITY AND MORTALITY IN THE ONGOING PANDEMIC. FUTURE RNA VIRUS EPIDEMICS AND PANDEMICS ARE INEVITABLE. NEW CLINICAL-TRIAL-READY ANTIVIRALS ARE URGENTLY NEEDED RNA VIRUSES OF PANDEMIC POTENTIAL. COVID-19 HAS FURTHER UNDERSCORED THE NEED FOR EARLY, GLOBAL ACCESS TO CLINIC-READY COMPOUNDS. BEYOND CORONAVIRUSES; FLAVIVIRUSES AND PICORNAVIRUSES ALSO CAUSE FREQUENT AND ONGOING EPIDEMICS WORLDWIDE AND HAVE NO EFFECTIVE THERAPEUTICS. MAINTAINING A PORTFOLIO OF NOVEL, CLINIC-READY THERAPEUTICS ARE CRITICAL FOR OUR FUTURE PANDEMIC PREPAREDNESS. THE AI-DRIVEN STRUCTURE-ENABLED ANTIVIRAL PLATFORM (ASAP) AVIDD CENTER WILL DEVELOP NOVEL CHEMICAL ASSETS THAT HAVE ANTIVIRAL ACTIVITY AGAINST THREE TARGET VIRAL FAMILIES. ASAP WILL LEVERAGE STATE-OF-THE-ART STRUCTURE-ENABLED TECHNOLOGIES CAPABLE OF LEVERAGING RECENT ADVANCES IN AI/ML AND COMPUTATIONAL CHEMISTRY IN IDENTIFYING, ENABLING, AND PROSECUTING DISCOVERY CAMPAIGNS AGAINST NOVEL VIRAL TARGETS. ASAP IS BUILT ON PRINCIPLES OF OPEN SCIENCE AND RAPID DISSEMINATION (ENABLED BY A DEDICATED DATA INFRASTRUCTURE CORE). ASAP BUILDS ON THE SUCCESSFUL COVID MOONSHOT, AN OPEN SCIENCE COLLABORATION THAT RECENTLY SECURED $11 MILLION FROM THE WELLCOME TRUST VIA THE WHO ACCESS TO COVID TOOLS ACCELERATOR (ACT-A) TO FUND PRECLINICAL DEVELOPMENT OF A NOVEL ORAL NONCOVALENT SARS-COV-2 ANTIVIRAL ACTING AGAINST THE MAIN PROTEASE (MPRO). BEGINNING WITH A HIGH-THROUGHPUT X-RAY FRAGMENT SCREEN, THE DISCOVERY TEAM SPENT JUST 18 MONTHS AND $1M TO REACH THE PRECLINICAL PHASE. ASAP WILL MIRROR THIS RAPID, COST-EFFICIENT APPROACH: AUTOMATED STRUCTURAL BIOLOGY AT DIAMOND LIGHT SOURCE (FRANK VON DELFT); AI/ML SYNTHESIS MODELS FROM POSTERA (ALPHA LEE); NANOSCALE CHEMISTRY AND COVALENT FRAGMENT LIBRARIES FROM NIR LONDON; MASSIVELY DISTRIBUTED FREE ENERGY CALCULATIONS ON FOLDING@HOME (JOHN CHODERA); AN INDUSTRIAL MEDICINAL CHEMISTRY TEAM LED BY MEDCHEMICA (ED GRIFFEN); AND ANTIVIRAL ASSAYS AND VIROLOGY EXPERTISE AT MOUNT SINAI (KRIS WHITE; ADOLFO GARCIA-SASTRE). ASAP AUGMENTS THIS SEASONED ANTIVIRAL DISCOVERY TEAM WITH NEW APPROACHES TO RESISTANCE-ROBUST TARGETING (KARLA KIRKEGAARD AND MATT BOGYO, STANFORD) AND DEEP MUTATIONAL SCANNING (JESSE BLOOM, FRED HUTCH). ASAP IS SUPPORTED BY THE DRUGS FOR NEGLECTED DISEASES INITIATIVE (DNDI) (PI BEN PERRY), AND LETTERS OF SUPPORT FROM TAKEDA, PFIZER, NOVARTIS, AND GRUPO INSUD. ASAP IMPACT: ASAP WILL BECOME THE NEXUS OF A ROBUST GLOBAL ANTIVIRAL DISCOVERY COMMUNITY. OUR OPEN SCIENCE APPROACH FOCUSES ON ENSURING GLOBAL, EQUITABLE ACCESS TO THERAPEUTICS TO COMBAT FUTURE PANDEMICS. WE AIM TO PRODUCE A ROBUST ANTIVIRAL PIPELINE CONSISTING OF 3 NEW PHASE I READY CANDIDATES, 6 LEAD OPTIMIZATION CAMPAIGNS, 9 FRAGMENT-TO-LEAD CAMPAIGNS, AND 10 STRUCTURE-ENABLED RESISTANCE-ROBUST VIRAL TARGETS. OUR ASSOCIATED DATA PACKAGES WILL ACCELERATE FOLLOW-ON DEVELOPMENT AND INVESTMENT.

COMPREHENSIVE CANCER CENTER PROGRAM AT FOX CHASE

THE IMMUNOBIOLOGY OF MARROW ALLOGRAFTS FOR LEUKEMIA

SPORE IN PROSTATE CANCER

PROGRAM PROJECT IN MODELS OF BREAST CANCER

NEW TARGETS FOR THERAPY FOR ADENOCARCINOMA OF THE LUNG

THE CCNY/MSKCC PARTNERSHIP FOR RESEARCH, TRAINING AND OUTREACH

MOLECULAR BASIS FOR GAMMA/DELTA T LINEAGE SPECIFICATION

SPORE IN SOFT TISSUE SARCOMA

THE SAN DIEGO EPIGENOME CENTER

GENOME-WIDE ASSOCIATION STUDY OF RADIATION EXPOSURE AND BILATERAL BREAST CANCER

MSKCC VIVARIUM

REACTOME: AN OPEN KNOWLEDGEBASE OF HUMAN PATHWAYS

CENTER FOR MAMMALIAN REGULATORY GENOMICS

SYSTEMS BIOLOGY OF DIVERSITY IN CANCER

SPORE IN OVARIAN CANCER

MSKCC CENTER FOR MOLECULAR IMAGING IN CANCER

COORDINATING CENTER FOR THE NCI SMALL CELL LUNG CANCER RESEARCH CONSORTIUM

MSK SPORE IN GENOMIC INSTABILITY IN BREAST CANCER

TRANSITION TO METASTATIC STATE: LUNG CANCER, PANCREATIC CANCER AND BRAIN METASTASIS

SPORE IN BLADDER CANCER

THE CSBC RESEARCH CENTER FOR CANCER SYSTEMS IMMUNOLOGY AT MSKCC

SPORE IN SOFT TISSUE SARCOMA

MSKCC CENTER FOR TRANSLATIONAL CANCER GENOMIC ANALYSIS

MSK SPORE IN LYMPHOMA

THE MEMORIAL SLOAN KETTERING CANCER CENTER SPORE IN LEUKEMIA - OVERALL ABSTRACT DESPITE RECENT ADVANCES IN THE TREATMENT OF ACUTE MYELOID LEUKEMIA (AML), THE MAJORITY OF AML PATIENTS RELAPSE FOLLOWING TREATMENT AND THE OVERALL FIVE-YEAR SURVIVAL RATE FOR ADULTS WITH AML REMAINS 25-29%. THUS, AN URGENT NEED TO IMPROVE THERAPY FOR AML PATIENTS REMAINS. THE MSK SPORE IN LEUKEMIA WILL LEVERAGE COLLECTIVE EFFORTS TO DEVELOP EFFECTIVE TARGETED THERAPIES AND IMMUNOTHERAPEUTIC APPROACHES FOR SEVERAL RECURRENT MOLECULAR SUBTYPES OF AML, INCLUDING SOME WHICH LACK THERAPEUTIC OPTIONS ENTIRELY. THE OVERALL TRANSLATIONAL AIMS OF THE MSK SPORE IN LEUKEMIA ARE TO 1) INTERROGATE GENETIC AND MOLECULAR PATHWAYS REQUIRED FOR AML INITIATION AND MAINTENANCE; 2) DEVELOP NOVEL TARGETED THERAPIES AND IMMUNOTHERAPEUTIC APPROACHES FOR AML BASED ON RECURRENT GENOMIC ALTERATIONS AND LEUKEMIA STEM-CELL (LSC) SPECIFIC MARKERS; AND 3) IDENTIFY AND VALIDATE THE MECHANISM OF ACTION, THERAPEUTIC EFFICACY, AND PREDICTORS OF RESPONSE/RESISTANCE OF MECHANISM-BASED THERAPIES FOR AML PATIENTS. TO PURSUE THESE AIMS, WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM WITH COMPLEMENTARY EXPERTISE IN THE CLINICAL MANAGEMENT OF AML, CANCER GENETICS, CANCER EPIGENETICS, FUNCTIONAL GENOMICS, MOLECULAR PATHOLOGY, BIOSTATISTICS, COMPUTATIONAL BIOLOGY, AND MULTIPLATFORM DATA INTEGRATION. WE WILL PURSUE THESE 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 PERFORM A CLINICAL TRIAL EXPLORING THE EFFICACY AND SAFETY OF COMBINING THE FLT3 INHIBITOR GILTERITINIB WITH MUTANT SELECTIVE IDH1/2 INHIBITORS FOR FLT3/IDH-MUTANT AML. PROJECT 2 WILL CHARACTERIZE THE CLINICAL, MOLECULAR, AND BIOLOGICAL FEATURES OF COMPLEX KARYOTYPE (CK) AML, FOR WHICH THERE IS NO TREATMENT, AND VALIDATE A NOVEL APPROACH TO TARGETING CK AML VIA INHIBITION OF THE METABOLIC ENZYME OXOGLUTARATE DEHYDROGENASE (OGDH). PROJECT 3 WILL EVALUATE A NOVEL THERAPEUTIC APPROACH FOR TARGETING COMMON, POOR PROGNOSIS SPLICEOSOMAL-MUTANT AML SUBTYPES VIA INHIBITION OF PROTEIN ARGININE METHYLTRANSFERASES IN PRECLINICAL MODELS AND A PHASE I/II CLINICAL TRIAL. PROJECT 4 WILL DETERMINE THE SAFETY AND EFFICACY OF A CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL APPROACH TARGETING A LEUKEMIA STEM CELL-SPECIFIC ANTIGEN WHILE SPARING NORMAL HEMATOPOIETIC STEM CELLS, SPECIFICALLY, A FULLY HUMANIZED CD371 TARGETING CAR T CELL PLATFORM BOLSTERED BY CONSTITUTIVE IL-18 SECRETION. ALL PROJECTS WILL BE SUPPORTED BY THE BIOSPECIMEN, BIOSTATISTICS, GENOMICS, AND BIOINFORMATICS SHARED RESOURCE CORES, WHICH WILL ASSIST WITH THE PREPARATION AND ANALYSIS OF HUMAN TISSUES AND GENOMIC, IMMUNE, AND CLINICAL DATA, AND AN ADMINISTRATIVE CORE TO ENSURE PROJECT INTEGRATION. FINALLY, PILOT PROJECTS IN THE DEVELOPMENTAL RESEARCH PROGRAM AND CAREER MENTORSHIP VIA THE CAREER ENHANCEMENT PROGRAM ARE FULLY INTEGRATED INTO THE SPORE TO ENSURE THAT A FUTURE GENERATION OF RESEARCHERS IS PREPARED TO FURTHER ADVANCE OUR LONG-TERM OBJECTIVES OF ENHANCING THERAPY, REDUCING THE MORBIDITY OF TREATMENTS, AND ULTIMATELY ELIMINATING THIS DISEASE AS A CAUSE OF PREMATURE DEATH

THE CENTER FOR TUMOR-IMMUNE SYSTEMS BIOLOGY AT MSKCC - THE CENTER FOR TUMOR-IMMUNE SYSTEMS BIOLOGY AT MSKCC SUMMARY THE ADVENT OF CANCER IMMUNOTHERAPIES BASED ON IMMUNE CHECKPOINT BLOCKADE (ICB) HAS REVOLUTIONIZED CLINICAL CARE IN MULTIPLE SOLID TUMOR TYPES AND DEMONSTRATED THE POWER OF THE IMMUNE SYSTEM TO TARGET AND ELIMINATE CANCER CELLS. DESPITE THESE BREAKTHROUGHS, THE EFFICACY OF ICB-BASED IMMUNOTHERAPY IS LIMITED TO A SUBSET OF CANCERS, AND EVEN IN TUMORS WHERE ICB IS NOW THE STANDARD OF CARE, ONLY A FRACTION OF PATIENTS ACHIEVE DURABLE COMPLETE RESPONSES. ADDRESSING THESE LIMITATIONS REQUIRES (1) IMPROVING OUR FUNDAMENTAL UNDERSTANDING OF TUMOR-IMMUNE INTERACTIONS IN IMMUNOLOGICAL CONTEXTS WHERE CURRENT IMMUNOTHERAPIES FAIL AND (2) DEVELOPING NOVEL STRATEGIES FOR ENHANCING RESPONSES IN CONTEXTS WHERE THEY HAVE ONLY PARTIAL SUCCESS. THE CENTER FOR TUMOR-IMMUNE SYSTEMS BIOLOGY AT MSKCC HAS ASSEMBLED A MULTI-DISCIPLINARY TEAM OF LEADING INVESTIGATORS IN COMPUTATIONAL BIOLOGY, IMMUNOLOGY, AND CANCER BIOLOGY TO TACKLE THESE CHALLENGES. THE CENTER IS ORGANIZED AROUND THREE RESEARCH PROJECTS THAT INTEGRATE COMPUTATIONAL AND EXPERIMENTAL STUDIES IN MOUSE MODELS AND MOLECULAR ANALYSES IN PATIENT TUMORS IN BOTH IMMUNOTHERAPY-RESISTANT AND -RESPONSIVE CONTEXTS, EXPLOITING NOVEL MACHINE LEARNING MODELING OF SINGLE-CELL MULTIOME, HIGHLY MULTIPLEXED OPTICAL IMAGING USING CONFOCAL IMMUNOFLUORESCENCE, AND SPATIAL TRANSCRIPTOMIC DATA SETS. WE WILL INVESTIGATE DISTINCT IMMUNE MICROENVIRONMENTS 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-ASSOCIATED MICROGLIA DICTATE MODES OF INVASION (PROJECT I); AND MISMATCH-REPAIR PROFICIENT PRIMARY COLON CANCER, WHERE TUMORS RESIDE IN A TOLERIZING MICROENVIRONMENT AND INTERACT WITH COMPLEX CELLULAR CIRCUITS OF REGULATORY AND CONVENTIONAL T CELLS, TOGETHER WITH METASTASES TO THE LYMPH NODE AND LIVER (PROJECT II). WE WILL ALSO CARRY OUT A SYSTEMS BIOLOGY INTERROGATION OF CANCER CELL DEATH MECHANISMS IN MODELS OF ICB-RESPONSIVE MELANOMA AND RENAL 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). A SHARED RESOURCE CORE WILL INTERACT WITH ALL THREE RESEARCH PROJECTS TO DEVELOP COMPUTATIONAL METHODS AND ESTABLISH TECHNOLOGIES FOR SPATIAL ANALYSES OF THE TUMOR-IMMUNE MICROENVIRONMENT. THESE STUDIES WILL ADVANCE OUR FUNDAMENTAL UNDERSTANDING OF TUMOR-IMMUNE ECOSYSTEMS IN ICB-REFRACTORY MICROENVIRONMENTS AND OF IMMUNE RESPONSES TO THERAPEUTICALLY INDUCED IMMUNOGENIC CANCER CELL DEATH IN ICB-RESPONSIVE SETTINGS, ULTIMATELY LEADING TO NOVEL IMMUNOTHERAPEUTIC TARGETS AND COMBINATION STRATEGIES. OUR TEAM WILL BUILD ON THE SUCCESSES OF OUR PREVIOUS CSBC U54 CENTER AWARD FOR THE CENTER FOR CANCER SYSTEMS IMMUNOLOGY AT MSKCC, WHICH PRODUCED NUMEROUS HIGH-IMPACT STUDIES AT THE FOREFRONT OF SYSTEMS BIOLOGY AND CANCER IMMUNOLOGY. OUR RESEARCH CENTER WILL ALSO CARRY OUT INNOVATIVE OUTREACH AND TRAINING ACTIVITIES TO DISSEMINATE RESEARCH FINDINGS IN TUMOR-IMMUNE SYSTEMS BIOLOGY AND TO TRAIN YOUNG SCIENTISTS IN THIS CRITICAL FIELD.

THE PROSTATE CANCER CLINICAL TRIALS CONSORTIUM: APPLICATION FOR COORDINATING CENTER WITH AFFILIATE CLINICAL RESEARCH SITES.

IMMUNOLOGIC APPROACHES TO OVARIAN CANCER

SYNERGISTIC ROLE OF SIGNALING AND EPIGENETICS IN LEUKEMIC TRANSFORMATION

SPORE IN THYROID CANCER

NETWORK LEAD ACADEMIC PARTICIPATING SITE: MEMORIAL SLOAN KETTERING CANCER CENTER

MSKCC PILOT CENTER FOR PRECISION DISEASE MODELING

DNA LIGASES IN MYCOBACTERIAL DNA REPAIR & PATHOGENESIS

THE PROSTATE CANCER CLINICAL TRIALS CONSORTIUM: APPLICATION FOR COORDINATING CENTER WITH CLINICAL RESEARCH SITE OPTION

IMMUNE MECHANISMS THAT CONTROL ECTROMELIA VIRUS INFECTION

THE MEMORIAL SLOAN KETTERING CANCER CENTER SPORE IN PANCREAS CANCER - PROJECT SUMMARY –OVERALL AN INCREASING NUMBER OF STUDIES INDICATE THAT SOME PATIENTS WITH PANCREAS DUCTAL ADENOCARCINOMA (PDAC) HAVE EXCEPTIONAL AND DURABLE RESPONSES TO THERAPY, BOTH STANDARD OF CARE AND, MORE RARELY TO IMMUNE-BASED THERAPIES. THERE IS A UNIQUE OPPORTUNITY TO UNDERSTAND THE GENETIC AND MOLECULAR MECHANISMS THAT UNDERLIE THESE EXCEPTIONAL RESPONSES OR DEFINE MECHANISMS OF INTRINSIC RESISTANCE TO THERAPY TO PROSPECTIVELY GUIDE CLINICAL MANAGEMENT AND ULTIMATELY INCREASE OVERALL SURVIVAL FOR ALL PATIENTS WITH PANCREAS CANCER. WE PROPOSE A SPECIALIZED PROGRAM OF RESEARCH EXCELLENCE IN PANCREAS CANCER AT MEMORIAL SLOAN KETTERING CANCER CENTER (THE MSK PANCREAS SPORE) TO LEVERAGE CUTTING-EDGE MOLECULAR KNOWLEDGE OF PANCREAS BIOLOGY AND CLINICAL INNOVATIONS TO ADVANCE TRANSLATIONAL RESEARCH IN PANCREAS CANCER. OUR LONG-TERM TRANSLATIONAL OBJECTIVE IS TO DEMONSTRATE THAT PROSPECTIVE, NEXT-GENERATION MOLECULAR APPROACHES COMBINED WITH STATE-OF-THE-ART CLINICAL MANAGEMENT CAN IMPROVE OUTCOMES OF PATIENTS WITH PANCREAS MALIGNANCIES. WE WILL SPECIFICALLY FOCUS ON THE MOST CHALLENGING DISEASE SETTINGS, LOCALLY ADVANCED AND METASTATIC PDAC, WHERE THE CLINICAL NEEDS ARE MOST PROFOUND. TO ACHIEVE THIS OBJECTIVE, WE PROPOSE THREE SPECIFIC AIMS. IN AIM 1, WE WILL LEVERAGE CURRENT STATE-OF- THE-ART AND NOVEL THERAPIES TO IMPROVE OUTCOMES FOR PATIENTS WITH STAGE III AND IV PDAC BY BUILDING UPON RECENT DEVELOPMENTS IN CYTOTOXIC AND TARGETED THERAPIES AND APPLY THESE AGENTS AND COMBINATIONS IN NOVEL DISEASE SETTINGS. IN AIM 2, WE WILL APPLY INNOVATION IN MOLECULAR CHARACTERIZATION OF PDAC TO DRIVE CLINICAL MANAGEMENT BY BUILDING UPON OUR EXTENSIVE EXPERTISE IN IMAGING, MOLECULAR DIAGNOSTICS, BIOMARKER DEVELOPMENT, AND SINGLE- CELL ANALYSES TO DEVELOP AND VALIDATE PROSPECTIVE BIOMARKERS OF TREATMENT RESPONSE AND RESISTANCE. IN AIM 3, WE WILL INVESTIGATE TWO AVENUES OF SURMOUNTING INTRINSIC IMMUNOTHERAPY RESISTANCE IN PDAC: SYNTHETIC LETHALITY OF COMBINATION PARP INHIBITION AND IMMUNE CHECKPOINT BLOCKADE, AND VIA ACTIVATION OF THE INTERLEUKIN-33 – GROUP 2 INNATE LYMPHOID CELL (IL33-ILC2) AXIS. WE EXPECT THAT SUCCESSFUL COMPLETION OF THESE AIMS WILL PROVIDE NEW INSIGHTS INTO PDAC BIOLOGY, ESTABLISH NEW COLLABORATIONS, ALTER TREATMENT PARADIGMS, AND ULTIMATELY IMPROVE DISEASE-FREE AND OVERALL SURVIVAL IN PANCREAS CANCER.

SAN DIEGO CENTER FOR 4D NUCLEOME RESEARCH

DISSECTING AND TARGETING LATENT METASTASIS

CENTER FOR SCALABLE KNOCKOUT AND MULTIMODAL PHENOTYPING IN GENETICALLY DIVERSE HUMAN GENOMES - ABSTRACT THE CORE MISSION OF THE MORPHIC PROGRAM IS TO DEFINE THE FUNCTION OF EVERY HUMAN GENE THROUGH THE CREATION OF A COMPREHENSIVE CATALOG OF NULL PHENOTYPES USING MULTICELLULAR SYSTEMS. THE IMPACT OF GENE LOSS ON COMPLEX PHENOTYPES IS STRONGLY INFLUENCED BY THE CELLULAR CONTEXT AND THE GENETIC BACKGROUND. THEREFORE, IT IS ESSENTIAL TO DEVELOP SCALABLE KNOCKOUT METHODS IN DIVERSE GENETIC BACKGROUNDS FOLLOWED BY ROBUST PHENOTYPING ASSAYS IN MULTICELLULAR SYSTEMS THAT ARE INFORMATIVE OF HUMAN BIOLOGY. OUR PRODUCTION CENTER WILL LEVERAGE OUR COLLECTIVE EXPERTISE IN HUMAN PLURIPOTENT STEM CELL (HPSC) GUIDED DIFFERENTIATION, ORGANOID ENGINEERING, GENE EDITING, AND OUR EXTENSIVE EXPERIENCE COMBINING LARGE-SCALE CRISPR-CAS9 KNOCKOUT PHENOTYPING WITH HPSC DIFFERENTIATION. WE PLAN TO CONDUCT EXTENSIVE CURATION AND QUALITY CONTROL TO SELECT A PANEL OF ~100 HPSC LINES, INCLUDING MOSTLY INDUCED PLURIPOTENT STEM CELL (IPSC) LINES AND SOME EMBRYONIC STEM CELL (ESC) LINES, FROM DIVERSE ANCESTRAL POPULATIONS, AND FROM MALES AND FEMALES TO GENERATE AN HPSC REPOSITORY FOR DISTRIBUTION. WE WILL FURTHER PRIORITIZE GENES AFFECTED IN NEURODEVELOPMENTAL AND METABOLIC DISORDERS (E.G., AUTISM AND DIABETES) FOR CONDUCTING KNOCKOUTS IN THESE DIVERSE HPSC LINES FOR SHARING WITH THE SCIENTIFIC COMMUNITY. FOR INVESTIGATION OF KNOCKOUT PHENOTYPES, WE WILL OPTIMIZE THREE DISTINCT MULTICELLULAR SYSTEMS, A MICROPATTERN-BASED GASTRULOID MODEL FOR EARLY TRI-GERM-LAYER DIFFERENTIATION, A DEFINED NEURO-GLIAL TRI- CULTURE SYSTEM, AND A 3D PANCREATIC ISLET-LIKE ORGANOID CULTURE. USING THESE MULTICELLULAR SYSTEMS WITH DIFFERENT LEVELS OF COMPLEXITY, WE WILL THEN CONDUCT EXTENSIVE PHENOTYPING ASSAYS IN A MULTITIERED SYSTEM TO ALLOW SCALED ANALYSIS BOTH IN TERMS OF THE GENES ANALYZED AND THE HPSC LINE BACKGROUND (REFLECTIVE OF THE HUMAN GENETIC BACKGROUND). PRIMARY HUMAN ISLETS WILL BE INCLUDED FOR SEVERAL PHENOTYPING ASSAYS TO TEST THE GENERALIZABILITY BEYOND THE HPSC SYSTEMS. WE EXPECT TO WORK WITH CONSORTIUM PARTNERS TO PRIORITIZE THE TARGET GENES FOR PHASE 1 OF THE MORPHIC PROJECT, DEVELOP STANDARDS FOR DATA AND RESOURCE SHARING, AND OPTIMIZE METHODS FOR JOINT ANALYSES. OUR PRODUCTION CENTER IS EXPECTED TO DELIVER A RICH RESOURCE OF KNOCKOUT HUMAN PLURIPOTENT STEM CELL LINES FROM DIVERSE GENETIC BACKGROUNDS, EXTENSIVE KNOCKOUT PHENOTYPING DATASETS IN MULTICELLULAR CONTEXTS THAT ARE INFORMATIVE OF DIVERSE HUMAN BIOLOGY, ROBUST AND SCALABLE KNOCKOUT AND PHENOTYPING PIPELINES ALONG WITH ASSOCIATED TRANSFERABLE METHODS, AND ESTABLISH STRONG USE CASES FOR THE MORPHIC CATALOG. THE OPTIMIZED MUTAGENESIS AND PHENOTYPING PIPELINES ALONG WITH THE SCALABLE METHODS WILL PAVE THE WAY FOR A FULL-SCALE MORPHIC CATALOG PRODUCTION EFFORT IN PHASE 2.

COORDINATING CENTER APPLICATION FOR PROSTATE CANCER RESEARCH PROGRAM CLINICAL CONSORTIUM AWARD

MECHANISMS OF DNA AND RNA TRANSACTIONS

SYSTEMS BIOLOGY OF MICROBIOME-MEDIATED RESILIENCE TO ANTIBIOTIC-RESISTANT PATHOGENS

MECHANISMS OF DNA REPLICATION, CHROMOSOME COMPACTION, AND CHROMOSOME UNLINKING

A NOVEL PATHWAY THAT PRODUCES SMALL REGULATORY RNAS IN DROSOPHILA

THE IMPACT OF DNA DAMAGE REPAIR ABNORMALITIES IN PROSTATE CANCER

THE PROSTATE CANCER CLINICAL TRIALS CONSORTIUM: APPLICATION FOR COORDINATING CENTER WITH AFFILIATE CLINICAL RESEARCH SITES

MSKCC -CORNELL CENTER FOR TRANSLATION OF CANCER NANOMEDICINES.

CANCER CHEMOTHERAPY TRAINING PROGRAM

ANNOTATING CANCER BIOLOGY THROUGH NON-INVASIVE MOLECULAR IMAGING

THE PROSTATE CANCER CLINICAL TRIALS CONSORTIUM: APPLICATION FOR COORDINATING CENTER WITH CLINICAL RESEARCH SITE OPTION

MSK PAUL CALABRESI CAREER DEVELOPMENT AWARD FOR CLINICAL ONCOLOGY

DECIPHERING THE GENOMICS OF GENE NETWORK REGULATION OF T CELL AND FIBROBLAST STATES IN AUTOIMMUNE INFLAMMATION - ABSTRACT NATURAL GENETIC VARIATION IMPACTS MOST HUMAN DISEASES, YET PREDICTING HOW REGULATORY VARIANTS CONTROL GENE EXPRESSION AND ULTIMATELY DISEASE PHENOTYPES POSES CONSIDERABLE CHALLENGES. FIRST, THE POLYGENIC INHERITANCE INFLUENCING MOST CONDITIONS REQUIRES CONSIDERATION OF A VAST NUMBER OF GENES AND REGULATORY ELEMENTS. THIS TASK IS CHALLENGED BY THE COMPLEXITY OF GENE REGULATION, WHERE 3D REGULATORY INTERACTIONS CAN LINK ENHANCERS AND GENES OVER LARGE GENOMIC DISTANCES. SECOND, MULTIPLE INTERACTING CELL TYPES ARE OFTEN DYSREGULATED IN DISEASE PATHOLOGY. THIS NECESSITATES AN UNDERSTANDING OF HOW THE COLLECTIVE VARIANTS ASSOCIATING WITH A DISEASE AFFECT EACH CELL TYPE INVOLVED IN THE DISEASE PROCESS AND SUBSEQUENTLY HOW THESE DYSREGULATED CELLULAR PHENOTYPES CROSSREGULATE AND DRIVE SUBSEQUENT CELLULAR STATES. IN THIS IGVF PROJECT, WE WILL USE RHEUMATOID ARTHRITIS (RA), A HUMAN AUTOIMMUNE INFLAMMATORY DISEASE, AS A CASE STUDY TO DEVELOP ROBUST MACHINE LEARNING MODELS OF GENE REGULATION TO DECIPHER THE IMPACT OF GENOMIC VARIATION ON MULTIPLE CELLULAR DRIVERS OF PATHOLOGY—NAMELY, INFLAMMATORY T CELL AND FIBROBLAST SUBSETS FOUND IN AFFECTED JOINT TISSUE. THE CHOICE OF RA IS MOTIVATED BY ITS PUBLIC HEALTH IMPORTANCE, SPECIFIED TARGET TISSUE, ACCESS TO CLINICAL SAMPLES, CONSIDERABLE KNOWLEDGE OF DISEASE-ASSOCIATED GENE LOCI, AND OUR TEAM’S COMPLEMENTARY EXPERTISE IN MACHINE LEARNING, RA PATHOPHYSIOLOGY, IMMUNOLOGY AND INFLAMMATION, AND SINGLE-CELL FUNCTIONAL GENOMICS. WE WILL DEVELOP AN ADVANCED MACHINE LEARNING FRAMEWORK TO MODEL THE EFFECTS OF ALLELIC VARIATION ON GENE REGULATORY NETWORKS BASED ON THE ANALYSIS OF EPIGENOMES, TRANSCRIPTOMES, AND CONNECTOMES OF MOUSE ACTIVATED T CELLS AND SYNOVIAL FIBROBLASTS AND EXTEND THESE MODELS TO RA PATIENT JOINT TISSUE AND PRIMARY CELLS. WE WILL TRAIN ALLELE-SPECIFIC GENE REGULATORY MODELS (GRMS) THAT ACCOUNT FOR LONG-RANGE REGULATORY INTERACTIONS BY INTEGRATING SINGLE-CELL TRANSCRIPTOME AND EPIGENOME (SC-MULTIOME) DATA WITH BULK 3D INTERACTOME ANALYSES. A NOTABLE FEATURE OF OUR APPROACH IS THAT WE LEVERAGE THE GENETIC DIVERSITY OF EVOLUTIONARILY DISTANT F1 HYBRID MICE TO PROVIDE ROBUST TRAINING DATA FOR THESE MODELS, AND THEN APPLY THESE ADVANCES TO THE HUMAN CONTEXT THROUGH TRANSFER LEARNING. HIGHLY PARALLELIZED PERTURB-SEQ EXPERIMENTS IN PRIMARY SYNOVIAL FIBROBLASTS FROM RA PATIENTS WITH SINGLE-CELL MULTIOMIC READOUTS WILL THEN BE USED TO EVALUATE AND REFINE REGULATORY MODELS AND TO TRAIN NETWORK MODELS THAT CONNECT GENE EXPRESSION PROGRAMS TO PHENOTYPE. FINALLY, WE WILL COMBINE SPATIAL AND SINGLE-CELL TRANSCRIPTOMICS CONDUCTED ON SAMPLES FROM RA INFLAMED JOINTS TO MODEL THE ORGANIZATION AND INTERACTIONS BETWEEN T CELLS AND SEDENTARY TISSUE-ORGANIZING FIBROBLASTS WITHIN LOCAL CELLULAR COMMUNITIES. THE PREDICTIVE GRMS THAT WILL BE GENERATED FROM OUR STUDY ALONG WITH THE EXPERIMENTAL SYSTEMS FOR HUMAN DISEASE WILL BE READILY TRANSFERRABLE TO OTHER POLYGENIC DISORDERS WHICH MUST CONSIDER COMPLEX REGULATORY GENOMIC NETWORKS FOR VARIOUS INTERACTING CELL TYPES IN AFFECTED TISSUES.

UNDERSTANDING THE MOLECULAR MECHANISMS REGULATING FUNGAL COLONIZATION AND DISEASE IN THE MAMMALIAN INTESTINAL NICHE - PROJECT SUMMARY THE FUNGAL COLONIZATION RESISTANCE (FUNCORE) PROGRAM PROJECT “UNDERSTANDING THE MOLECULAR MECHANISMS REGULATING FUNGAL COLONIZATION AND DISEASE IN THE MAMMALIAN INTESTINAL NICHE” FOCUSES ON DEVELOPING AN INTEGRATED AND PREDICTIVE MODEL OF THE MOLECULAR, CELLULAR, AND METABOLIC DETERMINANTS OF CANDIDA GASTROINTESTINAL (GI) COLONIZATION AND ITS RELATIONSHIP TO LIFE-THREATENING INVASIVE CANDIDIASIS. FUNCORE CONSISTS OF 3 PROJECTS AND 3 CORES AND COMBINES IN-DEPTH STUDIES OF HEMATOPOIETIC CELL TRANSPLANT PATIENTS WITH DEFINED CANDIDA COLONIZATION PHENOTYPES AND CURATED CLINICAL DATA WITH EXPERIMENTS IN REDUCTIONIST EXPERIMENTAL MODELS OF CANDIDA GI COLONIZATION. THE PATIENT COHORT SERVES AS A SOURCE FOR A LARGE CANDIDA STRAIN COLLECTION AND FOR FECAL METABOLITE ABUNDANCE MEASUREMENTS THAT ARE HARNESSED IN PROJECTS AND CORES. PROJECT 1 EMPHASIZES THE ROLE OF MORPHOLOGY, VIRULENCE FACTORS, AND STRAIN-SPECIFIC GENOMIC FEATURES ON C. ALBICANS AND C. PARAPSILOSIS GI COLONIZATION. PROJECT 2 CHARACTERIZES IMMUNE SIGNALING PATHWAYS AND CELL TYPES (PANETH CELLS, INNATE LYMPHOID CELLS) THAT MEDIATE CANDIDA COLONIZATION RESISTANCE. PROJECT 3 FOCUSES ON THE BACTERIAL MICROBIOTA AND THEIR BIOSYNTHETIC CAPABILITIES, WITH A FOCUS ON SHORT- AND MEDIUM-CHAIN FATTY ACIDS, TO DETERMINE DIRECT AND INDIRECT MECHANISMS OF COLONIZATION RESISTANCE. A GNOTOBIOTIC CORE ENABLES DEEP MECHANISTIC DISSECTION OF THE CONTRIBUTION OF INDIVIDUAL MOLECULAR, CELLULAR, IMMUNE PATHWAYS, AND COMMENSAL BACTERIA TO COLONIZATION PHENOTYPES. A MATHEMATICAL MODELING CORE TIES ALL 3 PROJECTS TOGETHER AND WILL GENERATE PREDICTIVE MODELS OF CANDIDA GI COLONIZATION THAT INCORPORATE SPECIFIC FUNGAL ATTRIBUTES, THE BACTERIAL MICROBIOTA AND METABOLITES, AND HOST IMMUNE PARAMETERS. MODELING OUTPUTS WILL BE ITERATIVELY TESTED AND REFINED IN COLLABORATION WITH THE EXPERIMENTAL PROJECTS TO EXPLORE THE OVERALL HYPOTHESIS THAT THE SYNERGY OF EXPERIMENTAL AND MODELING APPROACHES WILL REVEAL FUNGAL, IMMUNE-MEDIATED, AND METABOLIC DETERMINANTS OF CANDIDA GI COLONIZATION AND COLONIZATION RESISTANCE WHICH CAN INFORM AND BE HARNESSED FOR THERAPEUTIC STRATEGIES TO LIMIT INVASIVE CANDIDIASIS. AIM 1 WILL INVESTIGATE THE CANDIDA FUNCTIONAL CAPACITIES THAT PROMOTE GI COLONIZATION; AIM 2 WILL INTERROGATE HOST CELL NETWORKS AND COLONIZATION-RELEVANT METABOLITES AT THE HOST-CANDIDA INTERFACE; AIM 3 WILL DEVELOP AN INTEGRATIVE MODEL OF CANDIDA COLONIZATION RESISTANCE THAT IDENTIFIES ECOLOGIC, IMMUNE, AND METABOLIC TARGETS TO RESTORE AND ENHANCE CANDIDA COLONIZATION RESISTANCE. SUCCESSFUL COMPLETION OF THESE AIMS WILL BE SUPPORTED BY A STRONG ADMINISTRATIVE CORE MANAGEMENT PLAN TO FACILITATE COMMUNICATION AND COLLABORATION BETWEEN PROJECTS AND CORES. THE BREADTH AND COMPLEMENTARITY OF EXPERTISE, MULTIDISCIPLINARY APPROACHES, TRACK RECORD OF COLLABORATION, AND COMMITMENT TO ESTABLISH A MENTORED UNDERGRADUATE INTERNSHIP PROGRAM REPRESENT SIGNATURE FEATURES OF FUNCORE. INSIGHTS WILL INFORM BENCHTOP-TO-BED STRATEGIES TO FORMULATE NOVEL INTERVENTIONS THAT CAN SHAPE THE FUNGAL COMMUNITIES IN THE GI NICHE TO PREVENT INVASIVE CANDIDIASIS AND IMPROVE PATIENT OUTCOMES.

MECHANISMS OF ION CHANNELS IN CALCIUM SIGNALING

THE NATURAL KILLER CELL RESPONSE AGAINST MOUSE CYTOMEGALOVIRUS INFECTION

STUDIES ON ONCOPROTEIN-INDUCED FEEDBACK: BASIC AND THERAPEUTIC IMPLICATIONS

ISOLATION, CHARACTERIZATION AND TRANSLATIONAL DEVELOPMENT OF GLIOMA STEM CELLS

MECHANISTIC ANALYSIS OF T CELL POLARITY BY PHOTOACTIVATION OF SINGLE CELLS

MECHANISMS OF FIBROSIS AND LYMPHATIC DYSFUNCTION IN POST-SURGICAL LYMPHEDEMA

GENOMIC CONTROL OF GENE REGULATORY NETWORKS GOVERNING EARLY HUMAN LINEAGE DECISIONS - ABSTRACT PREDICTING THE IMPACT OF GENOMIC VARIATION REQUIRES QUANTITATIVE MODELING TO DECONSTRUCT THE INTERPLAY BETWEEN MULTIPLE INDIVIDUAL VARIANTS AND TO DETERMINE THEIR COMBINED EFFECTS ON GENE REGULATORY NETWORKS (GRNS) THAT CONTROL CELL STATE AND CELL FUNCTION. WE FOCUS ON THE GRNS THAT CONTROL EARLY HUMAN DEVELOPMENT AS A PARADIGM. ARGUABLY THE MOST IMPORTANT LINEAGE DECISION DURING MAMMALIAN DEVELOPMENT IS THE DECISION OF EPIBLAST CELLS TO EXIT THE PLURIPOTENT STATE (A STATE WHEN THE CELLS HAVE THE POTENTIAL TO GIVE RISE TO ALL SOMATIC CELLS AND GERM CELLS), AND DIFFERENTIATE INTO ONE OF THE THREE PRIMARY GERM LAYERS, THE ENDODERM, MESODERM, AND ECTODERM. THIS PLURIPOTENT STATE AND THE TRILINEAGE DIFFERENTIATION CAN BE CAPTURED USING CULTURED HUMAN EMBRYONIC STEM CELLS (HESCS). MUCH ATTENTION HAS FOCUSED ON THE GRNS UNDERLYING THE MAINTENANCE OF THE SELF-RENEWING PLURIPOTENT STATE, BUT THE GRNS GOVERNING HESC TRILINEAGE DIFFERENTIATION REMAIN LARGELY UNEXPLORED. WE PREVIOUSLY CONDUCTED GENOME-SCALE CRISPR/CAS SCREENS TO DISCOVER PROTEIN-CODING GENES THAT REGULATE THE TRANSITION OF HESCS TO DEFINITIVE ENDODERM. BASED ON THE GENOMIC AND GENETIC DATA AND MACHINE LEARNING (GKM-SVM SEQUENCE ANALYSIS), WE EXPANDED OUR INITIAL SIMPLE TWO TRANSCRIPTION FACTOR (TF) MODEL TO A MULTIPLE TF COOPERATIVE MODEL. HERE WE PROPOSE AN INTEGRATIVE APPROACH EXAMINING THE HESC TRANSITION TO DEFINITIVE ENDODERM, MESODERM AND NEUROECTODERM GERM LAYER IDENTITIES TO IMPROVE THE GENERALIZABILITY OF GRN MODELS. WE WILL PERFORM QUANTITATIVE GENOMIC AND PROTEOMIC MEASUREMENTS WITH HIGH TEMPORAL AND SINGLE-CELL RESOLUTION. THESE QUANTITATIVE MEASUREMENTS WILL BE COMBINED WITH PERTURBATION OF KEY GRN ELEMENTS, CORE TFS AND THEIR TARGET ENHANCERS, TO INFORM THE GENERATION OF DYNAMIC GRN MODELS. TO FURTHER IMPROVE THE PRECISION OF OUR NEW GRN MODELS, WE WILL MAP CELL TRAJECTORIES DURING STATE TRANSITIONS THROUGH LINEAGE TRACING COMBINED WITH SCRNA-SEQ. BEYOND HESC GUIDED DIFFERENTIATION, THE PHYSIOLOGICAL RELEVANCE OF ENHANCERS WILL BE FURTHER INTERROGATED IN HUMAN AND MOUSE ORGANOIDS (GASTRULOIDS) AND MOUSE EMBRYOS. WE WILL THEN APPLY INNOVATIVE NEW COMPUTATIONAL AND ALGORITHMIC METHODS TO OUR MULTIMODAL EXPERIMENTAL DATA TO GENERATE GRN MODELS, AIMING TO LEARN GENERALIZABLE PRINCIPLES UNDERLYING THE CONTRIBUTION OF GENOMIC VARIANTS TO CELLULAR AND ULTIMATELY ORGANISMAL PHENOTYPES. DEVELOPING GRN MODELS FOR THE EXIT OF PLURIPOTENCY AND THE ACQUISITION OF GERM LAYER IDENTITIES INVOLVES DYNAMIC MODELING OF THE CELL STATE TRANSITION, WHICH WILL NOT ONLY INFORM OUR UNDERSTANDING OF EARLY HUMAN DEVELOPMENT, BUT CAN ALSO SERVE AS THE BASIS FOR CONSTRUCTION OF GENERALIZABLE GRN MODELS FOR BIOLOGICAL TRANSITIONS DURING EMBRYONIC DEVELOPMENT, ADULT TISSUE HOMEOSTASIS AND REGENERATION AS WELL AS INAPPROPRIATE CELL FATE TRANSITIONS THAT OCCUR IN PATHOLOGICAL CONDITIONS SUCH AS CANCER.

TOWARD THE PRACTICE OF PRECISION MEDICINE: A BIOMARKER VALIDATION COORDINATING CENGER

ISOLATION OF NOVEL MUTATIONS AFFECTING THE MOUSE EMBRYO

TRAINING PROGRAM IN CANCER RESEARCH

ELUCIDATION OF IMMUNOGLOBULIN CLASS SWITCH RECOMBINATION AND SOMATIC HYPERMUTATIO

INTERROGATING THE EVOLUTIONARY DYNAMICS OF CANCER FOR CLINICAL BENEFIT AND ACTIONABILITY

MECHANISM, FUNCTION, AND EXPLOITATION OF INFLUENZA A VIRUS-ACTIVATED CELL DEATH

THE MSKCC-UW/FRED HUTCH PROSTATE CANCER DRUG RESISTANCE AND SENSITIVITY CENTER

ARYLEPOXAMIDES: A NEW CLASS OF POTENT, SAFER ANALGESICS

ENGRAILED GENES AND CEREBELLUM MORPHOLOGY, SPATIAL GENE EXPRESSION AND CIRCUITRY

COMPARATIVE MODELING OF EFFECTIVE POLICIES FOR COLORECTAL CANCER CONTROL

PREDICTIVE MODELS FOR SMALL-MOLECULE ACCUMULATION IN GRAM-NEGATIVE BACTERIA

PSYCHOSOCIAL PALLIATIVE AND COMMUNITY RESEARCH IN CANCER

ROLE OF TET2 MUTATIONS IN MALIGNANT TRANSFORMATION AND ACUTE MYELOID LEUKEMIA

INTERROGATING PROTEIN METHYLTRANSFERASES WITH INTEGRATED APPROACHES

GENETIC APPROACHES TO CANCER IMMUNOTHERAPY

STRUCTURAL BIOINFORMATICS OF PROTEINS AND PROTEIN COMPLEXES AND APPLICATIONS TO CANCER BIOLOGY

THE CBIOPORTAL FOR CANCER GENOMICS

THE TGF BETA SIGNALING PATHWAY IN DEVELOPMENT AND CANCER

THE CONTROL OF CENTRIOLE DUPLICATION AND DEGENERATION

ECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL SCIENCE CENTER (LTSC)

DOSE-RESPONSE OF AEROBIC TRAINING DURING TOTAL NEOADJUVANT THERAPY FOR LOCALLY ADVANCED RECTAL CANCER - PROJECT SUMMARY/ABSTRACT RANDOMIZED TRIALS DEMONSTRATE AEROBIC TRAINING (AT) ATTENUATES TREATMENT-INDUCED IMPAIRMENTS IN PHYSIOLOGICAL AND PSYCHOSOCIAL OUTCOMES IN A BROAD NUMBER OF CANCER PATIENT POPULATIONS. HOWEVER, WHETHER AT SPECIFICALLY IMPACTS THE TOLERABILITY OF CANCER TREATMENT IS LARGELY UNKNOWN. TO ADDRESS THIS FUNDAMENTAL KNOWLEDGE GAP IN EXERCISE-ONCOLOGY RESEARCH, THE OBJECTIVE OF THIS STUDY IS TO EVALUATE THE DOSE-RESPONSE OF AT ON TREATMENT TOLERABILITY AND RELATED OUTCOMES IN PATIENTS WITH LOCALLY ADVANCED RECTAL CANCER (LARC) INITIATING TOTAL NEOADJUVANT THERAPY (TNT). LARC IS AN IDEAL MODEL IN WHICH TO CONDUCT A DEFINITIVE TRIAL OF AT ON TREATMENT TOLERABILITY FOR SEVERAL REASONS: (1) HIGH RATE OF LARC DIAGNOSES ANNUALLY IN THE U.S. (>40,000), (2) POOR TOLERABILITY OF TNT (<60% OF PATIENTS COMPLETE THE RECOMMENDED REGIMEN), AND (3) STRONG BIOLOGICAL RATIONALE (TNT-INDUCED IMPAIRMENT IN HEMATOLOGICAL FUNCTION IS THE MAJOR CAUSE OF POOR TOLERABILITY, AND AT IS DEMONSTRATED TO ENHANCE HEMATOLOGICAL FUNCTION IN PRECLINICAL AND CLINICAL STUDIES). THEREFORE, IN THIS PHASE 2 RANDOMIZED TRIAL, A TOTAL OF 225 INACTIVE (<60 MINS OF MODERATE-INTENSITY EXERCISE/WK) PATIENTS WITH LARC SCHEDULED TO INITIATE TNT WILL BE STRATIFIED BY SEX (MALE VS. FEMALES) AND AGE (<55 YEARS VS. >55 YEARS) AND RANDOMLY ALLOCATED (1:1:1 RATIO) TO RECEIVE: 90 MINS/WEEK, 150 MINS/WEEK, OR 300 MINS/WEEK FROM PRE-TREATMENT TO PRE-SURGERY (~32 WEEKS). ALL AT DOSE REGIMENS WILL BE PRESCRIBED ACCORDING TO STANDARD AT PRINCIPLES AND IMPLEMENTED USING OUR DIGITAL AT PLATFORM PERMITTING ALL SESSIONS TO BE PERFORMED IN PATIENTS’ HOMES WITH REMOTE REAL-TIME MONITORING. WE WILL ADDRESS 3 SPECIFIC AIMS: AIM 1: DETERMINE DOSE-RESPONSE OF AT ON TNT TREATMENT TOLERABILITY. AIM 2: EVALUATE AT DOSE-RESPONSE ON HEMATOLOGICAL FUNCTION. AIM 3: EXPLORE AT DOSE-RESPONSE ON TUMOR CLINICAL OUTCOMES. THE PROPOSED STUDY DIRECTLY ADDRESSES AN UNMET CLINICAL NEED BY TESTING, FOR THE FIRST TIME, THE DOSE-RESPONSE EFFECTS OF AT ON MULTIPLE TREATMENT-RELATED OUTCOMES IN PATIENTS WITH LARC RECEIVING TNT. THE PROPOSED STUDY WILL IMPROVE BEHAVIORAL INTERVENTION PROTOCOLS FOR PATIENTS UNDERGOING CANCER TREATMENT BY USING OUR DIGITAL EXERCISE APPROACH THAT EXPANDS ACCESS TO AT FOR PATIENTS NOT RESIDING WITHIN CLOSE PROXIMITY OF A RESEARCH SITE. RECEIVING CANCER TREATMENT IS NOT A QUALIFYING CONDITION FOR EXERCISE THERAPY AND, AS SUCH, EXERCISE IS NOT CURRENTLY CONSIDERED A STANDARD ASPECT OF CANCER MANAGEMENT. THEREFORE, IF SUCCESSFUL, FINDINGS FROM THIS INVESTIGATION WILL ALSO SHIFT CLINICAL PARADIGMS REGARDING EXERCISE THERAPY IN CANCER BY ADDING TO A GROWING BODY OF EVIDENCE SUPPORTING INTEGRATION OF AT INTO STANDARD CLINICAL CANCER CARE.

UNCOVERING THE ROLE FOR MSI2 IN HEMATOPOIETIC STEM CELLS

MRNA CAPPING ENZYMES

UNDERSTANDING AND MIMICKING TCR RECOGNITION WITH THERAPEUTIC MONOCLONAL ANTIBODIES.

3'UTR-MEDIATED PROTEIN-PROTEIN INTERACTIONS DETERMINE PROTEIN FUNCTIONS

IMPACT OF SEX DIFFERENCES ON THE TRAJECTORY OF INTERACTOME DYSFUNCTIONS ACROSS THE AD SPECTRUM - ABSTRACT THE IMPACT OF SEX DIFFERENCES IN ALZHEIMER'S DISEASE (AD) REMAINS POORLY UNDERSTOOD, ESPECIALLY IN THE CONTEXT OF PROTEIN-PROTEIN INTERACTIONS WITHIN VULNERABLE REGIONS THAT DRIVE DYSFUNCTION. DESPITE GROWING APPRECIATION OF THE CLINICAL COURSE, PRESENTATION, AND SEVERITY OF AD, STUDIES OF SEX IMPACTING AD DEVELOPMENT AND PROGRESSION ARE LACKING. ALTHOUGH RECENT HIGH-THROUGHPUT AND BIOINFORMATICS TECHNOLOGIES HELP TO UNDERSTAND MOLECULAR AND GENETIC BASIS OF SEX DIFFERENCES IN AGING AND AD, RELIANCE ON STATIC `OMICS DATA REPRESENTING A DESCRIPTIVE INVENTORY OF BIOMOLECULES MEASURING CHANGES IN THEIR STOICHIOMETRY AT A GIVEN TIME AND CONDITION LIMITS FUNCTIONAL INSIGHTS. ANOTHER ROADBLOCK IS TRANSLATING THESE COMPLEX DATASETS INTO BIOLOGICAL INSIGHTS REQUIRES SOPHISTICATED COMPUTATIONAL ALGORITHMS, DIMINISHING ACCESS AND IMPACT TO THE BIOMEDICAL COMMUNITY AT LARGE. TO ADDRESS THESE LIMITATIONS THIS PROPOSAL INTRODUCES EPICHAPEROMICS, AN UNBIASED STATE-OF-THE-ART `OMICS APPROACH WE INVENTED TO GENERATE DIRECT ACCESS TO INTERACTOME PERTURBATIONS AND TO THE FUNCTIONAL OUTCOME OF SUCH CHANGES IN NATIVE BIOLOGICAL SYSTEMS. WE POSIT BY APPLYING EPICHAPEROMICS TO WELL-CHARACTERIZED POSTMORTEM HUMAN BRAINS THAT I) CAPTURE THE DISEASE TRAJECTORY, II) ENCOMPASS AD VULNERABLE AND LESS AFFECTED REGIONS, AND III) HAVE ROBUST PARALLEL INFORMATION ON PATIENT-SPECIFIC CORRELATES, WILL ENABLE RIGOROUS HYPOTHESIS- GENERATING ANALYSES ON POTENTIAL IMPACT OF STRESSORS AND VULNERABILITIES ON DISEASE TRAJECTORY, AND ON INTERACTOME AS WELL AS CONNECTOME DYSFUNCTIONS AS THEY OCCUR IN SEX-DEPENDENT MANNER. THROUGH THIS NOVEL APPROACH WE EXPECT TO DERIVE MECHANISTIC INNOVATION ON SPECIFIC DYSFUNCTIONS IMPACTED BY SEX DIFFERENCES LEADING TO INSIGHTS INTO SEX-PHENOTYPE RELATIONSHIPS NOT AVAILABLE THROUGH OTHER `OMICS PLATFORMS. BY EVALUATING, UNDERSTANDING, AND ANTICIPATING INTERACTOME CHANGES THROUGH EPICHAPEROME FORMATION IN RELATION TO SEX IMPACT (AIM 1) AND SUBSEQUENT STRAIGHTFORWARD COMPUTATIONAL ANALYSIS WITH WEB-BASED OUTPUT (AIM 2), FIRST-OF-A-KIND PROTEOME-WIDE INSIGHTS INTO THE IMPACT OF SEX DIFFERENCES ON INTERACTOME NETWORKS VULNERABILITIES AND DYSFUNCTIONS WITHIN THE HIPPOCAMPUS AND REGIONS OF THE DEFAULT MODE NETWORK IN RELATION TO THE RELATIVELY SPARED CEREBELLUM, BOTH ON THEIR NATURE AND TRAJECTORY, IN VULNERABLE CELLS AND BRAIN REGIONS WILL BE GENERATED. INFORMATION HOW STRESSORS AND VULNERABILITIES (E.G., GENES, ENVIRONMENT, HORMONAL STATUS) INTERACT AT CELL AND BRAIN CONNECTOME LEVELS TO PRODUCE HETEROGENEOUS PHENOTYPE MAPPING OF DISEASE VULNERABILITY WILL BE PRODUCED. WE POSIT A WHOLE NEW TREATMENT PARADIGM AVENUE WILL OPEN, PROVIDING A PREVIOUSLY UNAVAILABLE SEX-SPECIFIC PRECISION MEDICINE APPROACH TO AD BY UNDERSTANDING AND TARGETING THE INTERACTOME ACROSS THE AD SPECTRUM OF NO COGNITIVE IMPAIRMENT, MILD COGNITIVE IMPAIRMENT, AND AD DEMENTIA THROUGH STRESSOR AND VULNERABILITY ANALYSIS. RAW DATASETS AND DATA ANALYTICS FROM INTERACTOME NETWORK STUDIES WILL BE DEPOSITED INTO FREE-ACCESS PORTALS ACCESSIBLE BY THE SCIENTIFIC COMMUNITY FOR ADDITIONAL MINING AND HYPOTHESIS TESTING STUDIES. A WEB-BASED USER- INTERFACE WILL ALSO BE DESIGNED FACILITATING DATA PROCESSING AND VISUALIZATION.

A DATA COORDINATING CENTER FOR MODENCODE

CHAPEROME NETWORKS IN ALZHEIMER'S DISEASE - ABSTRACT THE GOAL OF THE PROPOSED PROJECT IS TO ADDRESS HOW NEURONAL STRESS TRIGGERED BY AMYLOID-BETA AND TAU OLIGOMERIC SPECIES INDUCES PROTEIN CONNECTIVITY DYSFUNCTIONS AND ALTERS PROTEIN-TO-NEURONAL CIRCUIT-TO-ORGAN LEVEL FUNCTION. OUR FOCUS IN ON SYNAPTIC DYSFUNCTION AND COGNITIVE DEFICITS IN ALZHEIMER'S DISEASE (AD). THE HYPOTHESIS BEHIND OUR INVESTIGATION IS THAT UPON ENTRY, THE MOLECULAR STRESS TRIGGERED BY AMYLOID-BETA AND TAU OLIGOMERIC SPECIES INDUCES A MALADAPTIVE REWIRING IN THE CONNECTIVITY, AND IN TURN THE FUNCTION OF LARGE SUBSETS OF DOWNSTREAM NEURONAL PROTEINS AND THEIR NETWORKS, THROUGH PATHOLOGIC CHAPEROME SCAFFOLDS TERMED EPICHAPEROMES. THIS HYPOTHESIS IS SUPPORTED BY PRELIMINARY DATA OBTAINED BY THE CHIOSIS LAB SHOWING THAT NEURONAL LINEAGES ARE ESPECIALLY PRONE TO FORM EPICHAPEROMES FOLLOWING STRESSORS, AND THAT MOST VULNERABLE TO EPICHAPEROMES ARE PROTEIN PATHWAYS WITH KEY ROLES IN SYNAPTIC PLASTICITY. ADDITIONAL PRELIMINARY EXPERIMENTS SUPPORTING FEASIBILITY OF OUR EXPERIMENTAL PLAN ARE PROVIDED BY STUDIES FROM THE ARANCIO LABORATORY AND OTHERS DEMONSTRATING THAT A AND TAU OLIGOMERS ALTER SYNAPTIC CONNECTIVITY LEADING TO MEMORY LOSS. OUR PRELIMINARY OBSERVATION THAT DISMANTLING THE PATHOLOGIC EPICHAPEROME STRUCTURES INTO NORMAL, FOLDING CHAPERONES REBALANCES PROTEIN NETWORK CONNECTIVITY AND FUNCTIONALITY TO THOSE SEEN IN PHYSIOLOGICAL CONDITIONS, ARE ALSO IN SUPPORT OF OUR SCIENTIFIC PREMISE. TO EXECUTE THESE STUDIES, WE USE IPSC-DERIVED CELLULAR MODELS AND MOUSE MODELS OF AD AND COMBINE THE SYNERGISTIC EXPERTISE OF DRS. ARANCIO (SYNAPTIC PLASTICITY, BIOLOGY OF AD), CHIOSIS (CHEMICAL BIOLOGY OF PATHOLOGIC PROTEIN NETWORKS, TRANSLATIONAL RESEARCH), FRASER (MOUSE MODELS OF AD AND AD BIOLOGY), ZHOU (IPSC MODELS IN DISEASE) AND MERTENS (CONSULTANT ON HIPSC AND IN-BASED CELLULAR MODELS FOR SYNAPTIC FUNCTION STUDY IN AD). WE EXPECT THAT OUR STUDIES WILL DELIVER PROTEOME-WIDE FUNCTIONAL INSIGHTS AND COMPREHENSIVE, MECHANISTIC UNDERSTANDING INTO HOW A AND TAU OLIGOMERS LEAD TO SYNAPTIC FAILURE AND COGNITIVE DEFECTS. IN ADDITION TO PROVIDING NEW INSIGHTS INTO AD BIOLOGY, OUR STUDIES HAVE IMMEDIATE TRANSLATIONAL APPLICATIONS. WITH AN EPICHAPEROME THERAPEUTIC DISCOVERED BY THE CHIOSIS LAB MOVING INTO PHASE 2 CLINICAL EVALUATION IN AD, HYPOTHESES TESTED WITHIN THE PRESENT PROPOSAL MAY HAVE IMMEDIATE IMPACT IN HUMAN AD.

THE CBIOPORTAL FOR CANCER GENOMICS - PROJECT SUMMARY GENOMIC SEQUENCING OF TUMOR SAMPLES IS NOW A ROUTINE COMPONENT OF CANCER CARE, PROVIDING UNPRECEDENTED INSIGHT INTO CANCER INITIATION, PROGRESSION, AND TREATMENT EFFECTS. ADDITIONALLY, NOVEL MOLECULAR PROFILING AND IMAGING TECHNIQUES ARE GAINING TRACTION, GENERATING EVER MORE DATA. ENSURING THAT THESE DATA SETS ARE EASILY ACCESSIBLE AND INTERPRETABLE TO SCIENTISTS AND CLINICIANS IS OF VITAL IMPORTANCE. TOWARDS THIS END, WE SEEK TO EVOLVE AND EXPAND THE CAPABILITIES OF THE CBIOPORTAL FOR CANCER GENOMICS, A UNIQUE PLATFORM THAT ENABLES INTERACTIVE EXPLORATORY ANALYSIS OF LARGE-SCALE CANCER GENOMIC DATA. THE CBIOPORTAL IS THE MOST WIDELY USED AND MOST HIGHLY CITED TOOL WITHIN THE CANCER GENOMICS COMMUNITY. THE PUBLIC SITE, WITH DATA FROM 325 CANCER STUDIES, IS ACCESSED BY >34,000 UNIQUE USERS EACH MONTH. THE CBIOPORTAL INSTANCE THAT SUPPORTS AACR PROJECT GENIE, A MULTI-INSTITUTIONAL DATA SHARING INITIATIVE, NOW HOSTS GENOMIC PROFILES FROM >120,000 TUMORS. SINCE THE SOFTWARE IS AVAILABLE UNDER AN OPEN SOURCE LICENSE, >65 CANCER CENTERS AND PHARMACEUTICAL COMPANIES HAVE INSTITUTIONAL INSTALLATIONS OF CBIOPORTAL TO ANALYZE THEIR OWN DATA. MULTIPLE INSTITUTIONS ARE MAKING CONTRIBUTIONS TO THE SOFTWARE, INCLUDING THE FIVE THAT ARE PART OF THIS APPLICATION (MEMORIAL SLOAN KETTERING CANCER CENTER, DANA-FARBER CANCER INSTITUTE, HARVARD MEDICAL SCHOOL, PRINCESS MARGARET CANCER CENTRE, AND CHILDREN’S HOSPITAL OF PHILADELPHIA). TO ENSURE THAT THIS VITAL RESOURCE CONTINUES TO AID THE CANCER RESEARCH COMMUNITY AND TO KEEP PACE WITH THE RAPIDLY ADVANCING FIELDS OF CANCER GENOMICS AND PRECISION CANCER MEDICINE, INCLUDING THE CONTINUING INCREASE IN THE NUMBER OF PROFILED TUMOR SAMPLES, WE PROPOSE TO ACTIVELY SUSTAIN AND EVOLVE THE CBIOPORTAL PLATFORM. SPECIFICALLY, WE PLAN TO MAKE IMPROVEMENTS ACROSS THE ENTIRE CBIOPORTAL SOFTWARE ARCHITECTURE (AIM 1); THIS INCLUDES SIGNIFICANT CHANGES TO ADDRESS KEY PERFORMANCE BOTTLENECKS, A NEW API CAPABLE OF SUPPORTING FEDERATED QUERIES, A NEW APP STORE, AND IMPROVEMENTS TO OUR CLOUD INFRASTRUCTURE AND DATA PIPELINES. WE WILL ALSO SUPPORT SEVERAL NEW MOLECULAR DATA TYPES, ADD TWO ENTIRELY NEW CBIOPORTAL VIEWS, DEVELOP NEW FEATURES FOR PRECISION ONCOLOGY, AND IMPROVE GENERAL USABILITY (AIM 2). WE PROPOSE TO CONTINUE FUNDING A GROUP OF CORE DEVELOPERS ACROSS FIVE INSTITUTIONS, EXPAND THE BASE OF CODE CONTRIBUTORS, AND CONTINUE TO COLLABORATE WITH THE HYVE TO SUPPORT BIOTECH AND PHARMACEUTICAL COMPANIES (AIM 3). FINALLY, TO MAXIMIZE USE IN THE SCIENTIFIC COMMUNITY, WE PLAN TO CONTINUE TO IMPROVE COMMUNITY OUTREACH, USER SUPPORT, AND TRAINING (AIM 4). THESE IMPROVEMENTS WILL BE NECESSARY TO ENSURE THAT CBIOPORTAL CONTINUES TO PROVIDE AN ESSENTIAL SERVICE FOR CANCER RESEARCH AND DEVELOPMENT OF NEW BIOMARKERS AND DRUGS, ESPECIALLY AS MORE CANCER CENTERS ARE USING THE CBIOPORTAL AS PART OF THEIR PRECISION MEDICINE PROGRAMS, AND AS PHARMACEUTICAL COMPANIES ARE USING IT FOR INTERNAL RESEARCH. WE EXPECT THAT, OVER THE NEXT FEW YEARS, THE CBIOPORTAL WILL CONTINUE TO HAVE A STRONG IMPACT ON ALL AREAS OF CANCER RESEARCH AND PATIENT CARE.

REACTOME: AN OPEN KNOWLEDGEBASE OF HUMAN PATHWAYS. - PROJECT SUMMARY/ABSTRACT WE SEEK RENEWAL OF THE CORE OPERATING FUNDING FOR THE REACTOME KNOWLEDGEBASE. REACTOME IS A MANUALLY CURATED, PEER-REVIEWED OPEN ACCESS BIOLOGICAL PATHWAY KNOWLEDGEBASE THAT CAN BE PUBLICLY USED AND REDISTRIBUTED BY ALL BIOLOGICAL RESEARCH COMMUNITY MEMBERS. THE REACTOME KNOWLEDGEBASE IS USED BY ACADEMIC, NONPROFIT AND FOR-PROFIT ENTITIES WORLDWIDE. SPECIFICALLY, REACTOME IS EMPLOYED BY GENOMICS AND PROTEOMICS RESEARCHERS, CLINICIANS, GENETICISTS, AND MOLECULAR BIOLOGISTS TO INTERPRET THE RESULTS OF LARGE-SCALE OMICS SCREENING PROJECTS, BY DATA SCIENTISTS AND BIOINFORMATICIANS TO DEVELOP NOVEL APPROACHES FOR KNOWLEDGE DISCOVERY AND MINING, AND BY SYSTEMS BIOLOGISTS TO BUILD PREDICTIVE MODELS OF NORMAL AND DISEASE PATHWAYS FOR DRUG DISCOVERY. OUR CURATORS, PHD-LEVEL SCIENTISTS, WORK CLOSELY WITH INDEPENDENT INVESTIGATORS WITHIN THE COMMUNITY TO ASSEMBLE HUMAN- AND MACHINE-READABLE DESCRIPTIONS OF HUMAN BIOLOGICAL PATHWAYS MANUALLY USING DEDICATED SOFTWARE TOOLS. EACH PATHWAY IS CHECKED AND PEER-REVIEWED PRIOR TO PUBLICATION TO ENSURE ITS FACTUAL ACCURACY AND COMPLIANCE WITH THE DATA MODEL. A SYSTEM OF EVIDENCE TRACKING ENSURES THAT ALL ASSERTIONS ARE SUPPORTED BY THE PRIMARY LITERATURE. REACTOME USES COMMUNITY-STANDARD CONTROLLED VOCABULARIES AND ONTOLOGIES TO INCREASE INTEROPERABILITY ACROSS RESOURCES. PATHWAYS ARE REVIEWED AND UPDATED REGULARLY. REACTOME PATHWAYS ARE AVAILABLE ON OUR WEB SITE FOR BROWSING, DOWNLOADING, AND MANIPULATION BY IN-HOUSE AND THIRD-PARTY ONLINE ANALYSIS TOOLS. THE PROJECT IS HIGHLY CITED IN THE LITERATURE, HAS BEEN USED REPEATEDLY TO MAKE SIGNIFICANT BIOLOGICAL DISCOVERIES, AND IS INCORPORATED INTO A LARGE NUMBER OF HIGH-IMPACT COMPUTATIONAL TOOLS AND RESOURCES. OVER THE NEXT FIVE YEARS, WE WILL: (1) EFFICIENTLY CURATE NORMAL AND DISEASE PROCESSES, AND EFFECTS OF GENETIC VARIATION AND DRUGS ON PROTEIN FUNCTION; (2) IMPROVE PATHWAY DATA ANALYSIS AND INPUT TOOLS TO INCREASE THE CURATION EFFICIENCY AND THE UTILITY OF REACTOME DATA IN LARGE-SCALE BIOLOGICAL DATA SCIENCE PROJECTS; (3) ENHANCE THE OPEN REACTOME PLATFORM; AND (4) CONDUCT ACTIVE OUTREACH EFFORTS TO FACILITATE USER ENGAGEMENT, COMMUNITY FEEDBACK, AND ADOPTION OF REACTOME.

SURGICAL ONCOLOGY RESEARCH TRAINING GRANT

MICROTUBULE REGULATION

MACROPHAGE DEVELOPMENT AND SPECIFICATION IN MICE.

RAD50: DNA DAMAGE & THE SUPPRESSION OF MALIGNANCY

TUMOR HYPOXIA IMAGING - LABORATORY AND CLINICAL STUDIES

HOMOLOGY-DIRECTED REPAIR: BRCA2 AND RAD51 PARALOGS

MOLECULAR CONTROL OF PROGENITOR CELL POLARITY AND CORTICAL NEUROGENESIS

FOX CHASE CLINICAL EPIDEMIOLOGY AND VALIDATION CENTER

A PERSONALIZED APPROACH USING HYPOXIA RESOLUTION TO GUIDE CURATIVE-INTENT RADIATION DOSE REDUCTION TO 30 GY: A NOVEL DE-ESCALATION PARADIGM FOR HPV-ASSOCIATED OROPHARYNX CANCERS

VACCINA VIRUS DNA TOPOISOMERASE

DNA DAMAGE & DNA REPLICATION: A COMPLEX RELATIONSHIP

COMPARATIVE MODELING OF COLORECTAL CANCER: INFORMING HEALTH POLICIES AND PRIORITIZING FUTURE RESEARCH

MODELING EFFECTIVE HEALTH POLICIES FOR COLORECTAL CANCER

MULTIDISCIPLINARY OVARIAN CANCER OUTCOMES GROUP (MOCOG)

MECHANISMS OF DNA REPLICATION

MECHANISM AND BIOLOGY OF WIDESPREAD DISTAL 3'UTR UTILIZATION IN THE CNS

MOBILIZATION OF NEURAL PRECURSORS IN THE CIRCULATING BLOOD OF PATIENTS WITH MULTIPLE SCLEROSIS

SOFT TISSUE SARCOMA PROGRAM PROJECT

UROLOGIC ONCOLOGY RESEARCH TRAINING GRANT

PHASE 2 STUDY OF SACITUZUMAB GOVITECAN-HZIYIN IN PATIENTS WITH PREVIOUSLY TREATED MESOTHELIOMAS

REGULATION OF CHROMOSOME SEGREGATION IN HUMAN CELLS

CANCER PREVENTION-INTERCEPTION TARGETED AGENT DISCOVERY PROGRAM AT FOX CHASE CANCER CENTER - PROJECT SUMMARY - OVERALL HEREDITABLE CANCER-PREDISPOSING MUTATIONS ARE ESTIMATED TO BE AN UNDERLYING CAUSE OF MORE THAN 100,000 ADULT CANCERS IN THE US EACH YEAR. FOR MANY HEREDITARY CANCER SYNDROMES, THE LIFE-TIME RISK OF DEVELOPING CANCER APPROACHES 100%. DESPITE REVOLUTIONARY ADVANCES IN “OMICS” TECHNOLOGIES, OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS REQUIRED TO SUPPORT THE ESTABLISHMENT OF PRECANCEROUS LESIONS AND PROMOTE EARLY TUMOR DEVELOPMENT REMAINS VERY LIMITED, THUS HINDERING THE DEVELOPMENT OF EFFICACIOUS INTERVENTIONS. A MULTIDISCIPLINARY TEAM OF ACCOMPLISHED INVESTIGATORS AT FOX CHASE CANCER CENTER (FCCC), WITH COMBINED EXPERTISE IN CANCER PREVENTION, HERITABLE CANCER RISK, CANCER BIOLOGY, MOLECULAR MODELING, AND DRUG DISCOVERY HAS BEEN ASSEMBLED TO ADDRESS THIS UNMET IN AN UNPRECEDENTED WAY. THE GOAL OF THE FCCC CAP-IT CENTER IS TO EFFECTIVELY COORDINATE THE DEVELOPMENT OF EFFICACIOUS MOLECULARLY-TARGETED AGENTS FOR PRECISION CANCER PREVENTION AND EARLY INTERCEPTION IN POPULATIONS AT HIGH RISK FOR CANCER. ALL STUDIES ARE FACILITATED BY THE UNIQUE RESOURCES OF THE FCCC RISK ASSESSMENT PROGRAM, WHICH INCLUDES OVER 12,000 FAMILIES AT HIGH RISK FOR CANCER AND 2000 CONFIRMED GERMLINE MUTATION CARRIERS. A COMPREHENSIVE PIPELINE FOR THE DEVELOPMENT OF AGENTS FOR CANCER PREVENTION AND INTERCEPTION IS PROPOSED THAT CONSISTS OF THREE WELL-DEVELOPED RESEARCH DOMAINS: TARGET VALIDATION (AIM 1), AGENT IDENTIFICATION AND SCREENING (AIM 2), AND PILOT IN VIVO EFFICACY STUDIES (AIM 3). EACH DOMAIN WILL BE LED BY A FCCC INVESTIGATOR, WHO IS A NATIONAL LEADER IN THE RESPECTIVE FIELD. TWO HIGHLY INNOVATIVE PROJECTS ARE PROPOSED THAT ILLUSTRATE THE ROBUSTNESS OF THE CAP-IT FRAMEWORK. PROJECT 1 (ENTERING AT TARGET VALIDATION) FOCUSES ON THE DEVELOPMENT OF A NEWLY-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 FOR EARLY INTERCEPTION IN THE FORMATION OF PANCREATIC CANCER. A NEUTRALIZING ANTIBODY AGAINST THE STROMAL PROTEIN NETRIN G1, THAT CAN REVERT FIBROBLASTS TO A TUMOR-SUPPRESSIVE PHENOTYPE, HAS BEEN DISCOVERED. ANTIBODIES WITH IMPROVED POTENCY WILL BE IDENTIFIED AND TESTED IN VIVO FOR THEIR ABILITY TO INTERCEPT THE PROGRESSION OF PANCREATIC INTRAEPITHELIAL NEOPLASIA. ALL CAP-IT RESEARCH AND TRAINING WILL BE STRONGLY SUPPORTED BY THE LEADERSHIP TEAM AND COORDINATING ACTIVITIES OF THE ADMINISTRATIVE CORE, LED BY DR. CLAPPER. EXPERTISE IN BIOSTATISTICS, BIOINFORMATICS, AND DATA MANAGEMENT WILL BE PROVIDED TO CAP-IT INVESTIGATORS BY AN INFORMATICS CORE, LED BY DR. ROSS. COLLABORATIONS AMONG THE NCI, FCCC AND OTHER CAP-IT CENTERS, AS WELL AS THE SHARING OF DATA AND RESOURCES THROUGH THE DATA AND 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, WHEN COMBINED WITH EXTENSIVE EXPERTISE IN DRUG DESIGN AND CANCER BIOLOGY, MAKES THIS CENTER UNIQUELY POISED TO BE INSTRUMENTAL IN THE DISCOVERY OF MOLECULARLY-TARGETED AGENTS TO PREVENT OR INTERCEPT EARLY ONCOGENESIS.

MATCHES: MAKING TELEHEALTH DELIVERY OF CANCER CARE AT HOME EFFECTIVE AND SAFE - PROJECT SUMMARY/ABSTRACT THE MATCHES (MAKING TELEHEALTH DELIVERY OF CANCER CARE AT HOME EFFECTIVE AND SAFE) TELEHEALTH RESEARCH CENTER AIMS TO BUILD THE EVIDENCE BASE NECESSARY TO ESTABLISH BEST PRACTICES FOR TELEHEALTH-ENABLED CANCER CARE. THE OVERARCHING GOAL OF THE CENTER IS TO CREATE A RESEARCH HUB THAT GENERATES EVIDENCE, TRAINS INVESTIGATORS, AND DEVELOPS THE RESEARCH METHODS REQUIRED TO IGNITE THE FIELD OF PRECISION CANCER CARE DELIVERY. PRIOR WORK DEMONSTRATES THAT ONCOLOGY-FOCUSED TELEHEALTH CAN ACHIEVE FAVORABLE OUTCOMES, BUT LARGE-SCALE TRIALS HAVE BEEN LIMITED TO SPECIFIC CONTEXTS LIKE PALLIATIVE CARE OR SURVIVORSHIP. ADOPTION HAS BEEN CONSTRAINED BY RESTRICTED REIMBURSEMENT. THE MATCHES CENTER WILL HELP REMEDIATE THIS EVIDENCE GAP BY EXECUTING PROSPECTIVE TRIALS, CONDUCTING OBSERVATIONAL ANALYSES, AND TRAINING TRANSDISCIPLINARY RESEARCHERS. OUR RESEARCH THEME FOCUSES ON THE INTEGRATION OF MULTI-LAYERED DATA FROM TELEHEALTH PLATFORMS, PATIENT PORTALS, MOBILE TRACKING DEVICES, AND THE ELECTRONIC MEDICAL RECORD TO DEVELOP ANALYTIC METHODS THAT SUPPORT PERSONALIZED CARE. WE AIM TO DEVELOP A NEW PARADIGM IN ONCOLOGY—PRECISION DELIVERY—WITH THE ULTIMATE GOAL OF MATCHING INDIVIDUAL PATIENTS WITH THE MOST BENEFICIAL COMBINATION OF CLINIC-BASED OR TELEHEALTH-SUPPORTED HOME-SETTING CARE AT THE APPROPRIATE TIME—ALL BASED ON THE TOTALITY OF DYNAMICALLY AVAILABLE DATA. WE WILL ACCOMPLISH THIS GOAL BY APPLYING DATA SCIENCE METHODS—INCLUDING NIMBLE TRIAL DESIGNS AND MACHINE LEARNING—THAT HAVE HAD LIMITED APPLICATION TO TELEHEALTH TO DATE. BY ESTABLISHING A RESEARCH HUB THAT NURTURES INVESTIGATORS ACROSS DISCIPLINES AND PROVIDES TRAINING, TOOLS, DATA, ANALYTIC METHODS, AND VENUES FOR SHARING KNOWLEDGE AND BUILDING PARTNERSHIPS, WE EXPECT TO ACCELERATE PROGRESS IN THE SCIENCE OF CARE DELIVERY. OUR SPECIFIC AIMS ARE 1) TO CONDUCT IMPACTFUL PRAGMATIC TRIALS OF TELEHEALTH IN ONCOLOGY, 2) TO ANALYZE A LARGE EXISTING CACHE OF MULTIDIMENSIONAL OBSERVATIONAL DATA CHARACTERIZING TELEHEALTH UTILIZATION AND OUTCOMES, 3) TO TRAIN INVESTIGATORS AND EQUIP THEM WITH THE SKILLS NECESSARY TO INNOVATE WITHIN AN EVIDENCE-BASED FRAMEWORK, AND 4) TO INTEGRATE TELEHEALTH WITH OTHER DATA STREAMS AND CREATE AND APPLY ANALYTIC METHODS TO TRANSFORM THE FIELD OF PRECISION CARE DELIVERY. AN ADMINISTRATIVE CORE WILL COORDINATE ACTIVITIES AND ENGAGE FEEDBACK FROM INTERNAL AND EXTERNAL STAKEHOLDERS—INCLUDING PATIENTS AND THE ONCOLOGY WORKFORCE. OUR CLINICAL PRACTICE NETWORK SERVES AS AN INNOVATION LABORATORY AND COMPRISES 7 OUTPATIENT CLINICS IN NY AND NJ WITH A SHARED INFORMATICS ECOSYSTEM INCLUDING TELEHEALTH CAPACITY, DIGITAL MONITORING, AND A HIGHLY TRAFFICKED PATIENT PORTAL. THIS WILL ENABLE US TO LAUNCH AND EXECUTE A LARGE PRAGMATIC TRIAL COMPARING IN-PERSON CARE TO TELEHEALTH, WITH RESOURCES DESIGNED TO SUPPORT HOME-BASED CARE USING A CLUSTER-RANDOMIZED DESIGN. THE RESEARCH & METHODS CORE WILL SUPPORT THE CENTER BY APPLYING DATA SCIENCE METHODS TO EXTRACT AND SYNTHESIZE INSIGHTS FROM TELEHEALTH AND OTHER DATA STREAMS TO DEVELOP METHODS RELEVANT TO ADVANCING PRECISION CANCER CARE DELIVERY AND THE GOALS OF EQUITY, EFFICACY, AND EFFICIENCY TO CREATE AN OPTIMAL EXPERIENCE FOR PEOPLE BEING TREATED FOR CANCER.

MOLECULAR PATHOPHYSIOLOGY OF THYROID CELL GROWTH

NOVEL THERAPEUTIC DEVELOPMENT FOR SMALL CELL LUNG CANCER - PROJECT SUMMARY / ABSTRACT SMALL CELL LUNG CANCER (SCLC) IS CHARACTERIZED BY RAPID GROWTH, EARLY DISSEMINATION, AND EXCEPTIONALLY POOR PROGNOSIS. THE RUDIN LABORATORY HAS FOCUSED ON THE STUDY OF SCLC FOR OVER 2 DECADES USING A FULLY INTEGRATED PLATFORM OF BASIC DISCOVERY AND CLINICAL TRANSLATIONAL RESEARCH. OUR LABORATORY HAS DRIVEN FUNDAMENTAL ADVANCES IN THE UNDERSTANDING AND CHARACTERIZATION OF SCLC. WE HAVE EXCELLED IN SUCCESSFULLY TRANSLATED MANY DISCOVERIES MADE BY OUR GROUP INTO CLINICAL TESTING, INCLUDING MANY ACTIVE TRIALS CURRENTLY BEING CONDUCTED BY OUR CLINICAL TEAM. CLOSING THE CIRCLE, WE ARE ALSO DEEPLY ENGAGED IN THE MOLECULAR CHARACTERIZATION OF BIOSPECIMENS FROM PATIENTS RECEIVING THESE NOVEL THERAPIES, TO BETTER INFORM NEW DIRECTIONS OF LABORATORY RESEARCH WHILE MAINTAINING DIRECT DISEASE RELEVANCE. IN THIS R35 WE WILL FOCUS PRIMARILY ON THREE MAIN AREAS OF FUTURE FOCUS FOR OUR GROUP. (1) RECENT EXTENSIVE SINGLE CELL PROFILING DATA FROM OUR LABORATORY HAS DEFINED THE EXCEPTIONAL INTRA- AND INTER-TUMORAL HETEROGENEITY OF PRIMARY HUMAN SCLC. WE HAVE IDENTIFIED A KEY SUBPOPULATION WITH STEM-LIKE CAPACITY, PRESENT IN TUMORS OF ALL SCLC SUBTYPES, AND ALSO IDENTIFIED AND CHARACTERIZED A NOVEL TUMOR-INFILTRATING MACROPHAGE SUBTYPE EXCLUSIVELY ASSOCIATED WITH SCLC. THE STEM-LIKE CELL POPULATION EXPANDS PROGRESSIVELY IN NODAL AND DISTANT METASTASES, AND HIGH FRACTION OF THIS SUBPOPULATION CONFERS A STRIKINGLY POOR CLINICAL PROGNOSIS. DEFINING, CHARACTERIZING, AND TARGETING THESE NOVEL CELL TYPES COULD HAVE A TRANSFORMATIVE IMPACT ON PATIENTS WITH SCLC. (2) WE HAVE A LONG-STANDING INTEREST IN LINEAGE PLASTICITY, INCLUDING HISTOLOGIC TRANSFORMATION FROM LUNG ADENOCARCINOMA TO SCLC, AND TUMOR EVOLUTION BETWEEN SCLC SUBTYPES. WE NOW HAVE MULTIPLE RELEVANT TOOLS IN HAND TO DISSECT THE BIOLOGY OF LINEAGE PLASTICITY IN LUNG CANCER, INCLUDING PATIENT-DERIVED XENOGRAFT (PDX) MODELS OF LUNG ADENOCARCINOMA THAT UNDER DIFFERENT CONDITIONS TRANSITION TO DIFFERENT SUBTYPES OF SCLC. WE WILL DEEPLY ANALYZE THE DRIVERS OF SCLC TRANSFORMATION AS A MECHANISM OF TUMOR ESCAPE AND ACQUIRED RESISTANCE IN LUNG CANCER. THESE DATA WILL INFORM APPROACHES TO PREVENT OR RESTRICT LINEAGE PLASTICITY AS A DRIVER OF THERAPEUTIC RESISTANCE. (3) WE HAVE DEVELOPED NEW TECHNOLOGY ALLOWING CONTROLLED IN VIVO CRISPR/CAS9 GENE EDITING IN PDX. WE WILL ADAPT THIS SYSTEM TO CONDUCT FOCUSED SCLC GENETIC DEPENDENCY SCREENS IN VIVO USING A GUIDE RNA LIBRARY COVERING THE DRUGGABLE GENOME. APPLIED ACROSS ALL SUBTYPES OF SCLC, THIS APPROACH WILL DEFINE NOVEL THERAPEUTIC TARGETS FOR THIS RECALCITRANT MALIGNANCY.

REGULATION OF THE DNA DAMAGE RESPONSE BY THE MRE11 COMPLEX

ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA

EXPLOITING EPIGENETIC VULNERABILITIES IN BREAST CANCERS WITH CHROMOSOMAL INSTABILITY

TOWARDS TARGETING THE LYMPHOMA MICROENVIRONMENT

MECHANISMS AND FUNCTION OF MYONUCLEAR POSITIONING

MOLECULAR TARGETING OF DEVELOPMENTAL CANCERS IN CHILDREN

ROLE OF MICROGLIA SOMATIC VARIANTS IN NEURODEGENERATIVE DISEASES

NOVEL REGULATORY MECHANISMS UNDERLYING INSIDE-OUT INTEGRIN ACTIVATION

INITIATION OF THE IMMUNE RESPONSE TO ASPERGILLUS FUMIGATUS

ALPHA-PARTICLE IMMUNOTHERAPY OF CANCER

MECHANISMS OF LIPID DROPLET PROTEIN TARGETING

RNA-DIRECTED TARGETING OF AID IN IMMUNITY AND GENOMIC INTEGRITY

[18F]-PU-AD EPICHAPEROME PET IMAGING PROBE - ABSTRACT DISCOVERY OF HUMAN RADIOTRACERS THAT SERVE AS COMPANION DIAGNOSTICS AND/OR AID IN UNDERSTANDING ABNORMAL BIOLOGICAL PROCESSES THAT UNDERLIE COGNITIVE DISORDERS, SUCH AS ALZHEIMER'S DISEASE (AD) AND OTHER BRAIN DISORDERS IS AN AREA OF HIGH TRANSLATIONAL PRIORITY TOWARDS KEY MILESTONES TIED TO THE IMPLEMENTATION OF THE NATIONAL PLAN TO ADDRESS ALZHEIMER'S AND RELATED DEMENTIAS AND A SPECIFIC REQUIREMENT OF PAR-20-038. OUR STUDY PROPOSES THE DISCOVERY AND EVALUATION OF A RADIOPHARMACEUTICAL AGENT FOR THE POSITRON EMISSION TOMOGRAPHY (PET) IMAGING OF EPICHAPEROMES, EMERGING TARGETS IN AD. EPICHAPEROMES, LONG-LIVED OLIGOMERIC PROTEIN SCAFFOLDING PLATFORMS, ARE AMONG THE EARLIEST MEDIATORS OF AD PATHOGENESIS. THEY NEGATIVELY IMPACT THE INTERACTIONS OF PROTEINS IMPORTANT FOR NEURONAL FUNCTION, SUCH AS SYNAPTIC PLASTICITY, CELL-TO-CELL COMMUNICATION, PROTEIN TRANSLATION, CELL CYCLE RE-ENTRY, AXON GUIDANCE, METABOLIC PROCESSES AND INFLAMMATION, LEADING TO PROTEOME-WIDE DEFECTS IN PROTEIN-PROTEIN INTERACTION NETWORKS, AND IN TURN CELL- AND BRAIN-NETWORK DYSFUNCTION AND COGNITIVE DECLINE. WE DISCOVERED BOTH EPICHAPEROME DRUGS (EG. PU-AD) AND COMPANION DIAGNOSTICS (EG. [124I]-PU-AD PET) AND TRANSLATED THEM TO CLINIC. TO IMAGE EPICHAPEROMES, WE DISCOVERED [124I]-PU-AD, A [124I]- LABELED EPICHAPEROME PROBE. IN A PILOT FEASIBILITY CLINICAL STUDY, [124I]-PU-AD PROVIDED PROOF-OF-PRINCIPLE THAT EPICHAPEROMES ARE IMAGEABLE AND QUANTIFIABLE IN PATIENTS BY PET. IN PRECLINICAL MODELS, IT DEMONSTRATED THAT EPICHAPEROMES FORM IN AD IN A DISEASE-RELEVANT REGION- AND AGE-DEPENDENT MANNER. THE NEXT STEP IS TO MAKE EPICHAPEROME IMAGING PROBES PRACTICAL FOR WIDESPREAD CLINICAL USE. WE POSIT REPLACING THE 124I LABEL WITH 18F WILL SIGNIFICANTLY IMPROVE SENSITIVITY, SPATIAL AND TEMPORAL IMAGE QUALITY, REDUCE RADIATION BURDEN AND IMAGING TIMES, IMPROVE PRODUCTION COSTS AND AVAILABILITY, THUS INCREASING THE CLINICAL APPLICABILITY OF THE PROBE. WE HERE PROPOSE A PLAN FOR THE DISCOVERY OF THE 18F EPICHAPEROME PET IMAGING AGENT WITH EMPHASIS ON STEPS SUCH AS SYNTHESIS, IDENTIFICATION OF LEAD CANDIDATES, TRACER CHARACTERIZATION, SAFETY, DOSING, PRECLINICAL VALIDATION AND IND-ENABLING STUDIES FOR A PROPOSED FUTURE EXPLORATORY INVESTIGATIONAL NEW DRUG APPLICATION. WE ASSEMBLE A MULTIDISCIPLINARY TEAM WITH A HISTORY OF SUCCESSFUL COLLABORATIONS (>40 PAPERS, >20 PET TRACERS IN CLINIC) AND DESIGNED 3 SPECIFIC AIMS TO ACCOMPLISH OUR GOAL: AIM 1. IDENTIFY F-CONTAINING EPICHAPEROME PROBES WITH FAVORABLE AFFINITY, SELECTIVITY AND BBB PERMEABILITY; AIM 2. INVESTIGATE THE PROBE'S SPECIFICITY AND SENSITIVITY IN DETECTING EPICHAPEROME-MEDIATED DYSFUNCTION IN AD MOUSE MODELS; AND AIM 3. PERFORM IND-ENABLING STUDIES FOR A PROPOSED EXPLORATORY INVESTIGATIONAL NEW DRUG APPLICATION. OUTCOMES OF THIS WORK ARE NOVEL PET PROBES FOR USE AS PRECISION MEDICINE TOOLS TO IMAGE IN VIVO EARLY MOLECULAR DYSFUNCTION IN THE BRAIN AND AS COMPANION DIAGNOSTICS FOR EPICHAPEROME TARGETED THERAPIES, BOTH RESEARCH AREAS OF HIGH TRANSLATIONAL PRIORITY.

NEW; TITLE: INTEGRATED MANHATTAN PROJECT FOR EXCELLENCE IN RADIOCHEMISTRY (IMPER); PI: JASON LEWIS

ALLOREACTIVE AND AUTOREACTIVE IMMUNE-MEDIATED MECHANISMS OF IMPAIRED EPITHELIAL REGENERATION IN THE GI TRACT

SELF PEPTIDES BOUND TO MHC CLASS II IN T CELL SELECTION

MOLECULAR MECHANISMS OF DRUG RESISTANCE IN PRIMARY BRAIN TUMORS

LEVERAGING OBSERVATIONAL (REAL WORLD) DATA TO ADVANCE PRECISION ONCOLOGY - OVERALL ABSTRACT LEVERAGING OBSERVATIONAL (REAL WORLD) DATA TO ADVANCE PRECISION ONCOLOGY PRINCIPAL INVESTIGATOR: CHARLES SAWYERS, MEMORIAL SLOAN KETTERING CANCER CENTER PRECISION ONCOLOGY IS A FIRMLY ESTABLISHED PILLAR IN THE PRACTICE OF CANCER MEDICINE, BUT WE NOW RECOGNIZE NEW CHALLENGES TO ITS BROAD IMPLEMENTATION. THESE INCLUDE: (I) HETEROGENEITY IN RESPONSE TO PRECISION ONCOLOGY DRUGS IN PATIENTS WITH IDENTICAL DRIVER MUTATIONS, (II) DIFFERENCES IN DRIVER MUTATION FREQUENCIES IN PATIENTS FROM DIFFERENT ETHNICITIES, WITH IMPLICATIONS FOR ENSURING OPTIMAL TREATMENT, (III) INCREASED SUBTYPING OF CANCER INTO HUNDREDS OF “RARE” DISEASES, AND THE RESULTANT OPERATIONAL CHALLENGES IN CLINICAL TRIAL DESIGN AND EXECUTION, AND (IV) A LIMITED UNDERSTANDING OF HOW TO EFFECTIVELY LEVERAGE OBSERVATIONAL (REAL WORLD) DATA TO ADDRESS THESE CHALLENGES. THE INVESTIGATORS IN THIS P01 PROGRAM HAVE HAD A LONGSTANDING COLLABORATION OVER THE PAST 8 YEARS, HELPING TO BUILD A LARGE (>148,000 PATIENTS), INTERNATIONAL CLINICO-GENOMIC CANCER REGISTRY KNOWN AS AACR PROJECT GENIE. WE HAVE COME TOGETHER TO INVESTIGATE THESE ISSUES AND PROPOSE FOUR HIGHLY INTEGRATED PROJECTS RELATED TO THESE THEMES. PROJECT 1 SEEKS TO OVERCOME METHODOLOGIC BARRIERS IN THE ANALYSIS OF OBSERVATIONAL CLINICO-GENOMIC DATA. PROJECT 2 WILL ADDRESS THE ROLE OF GENETIC ANCESTRY IN PRECISION ONCOLOGY OUTCOMES AND POTENTIAL INEQUITIES IN HOW PRECISION ONCOLOGY DIAGNOSTIC TESTS ARE DEVELOPED. PROJECT 3 WILL USE REAL WORLD EVIDENCE TO INFORM CLINICAL DECISIONS FOR THE TREATMENT OF CANCER PATIENTS THAT CANNOT BE ADDRESSED USING CONVENTIONAL CLINICAL TRIAL DATASETS AND WILL OPTIMIZE THE REPORTING OF THESE FINDINGS USING THE ONCOKB KNOWLEDGE BASE. THE PROJECTS WILL BE SUPPORTED BY THE CURATION AND STATISTICAL ANALYSIS CORE (DATA ABSTRACTION AND BIOSTATISTICS SUPPORT); THE MOLECULAR PATHOLOGY AND BIOINFORMATICS CORE (MOLECULAR PROFILING AND DATA CAPTURE); AND THE ADMINISTRATIVE CORE (INCORPORATING EXISTING GENIE INFRASTRUCTURE FOR DATA SHARING, COMMUNICATIONS, AND ADMINISTRATIVE SUPPORT). OUR PROPOSAL IS HIGHLY SYNERGISTIC AS IT BRINGS TOGETHER A MULTI-INSTITUTIONAL TEAM OF DISTINGUISHED INVESTIGATORS IN POPULATION SCIENCE, POPULATION GENETICS, CANCER GENOMICS AND EXPERIMENTAL THERAPEUTICS, WITH A SUBSTANTIAL TRACK RECORD OF COLLABORATIVE INTERACTIONS, WHO WILL WORK TOGETHER TO ADDRESS THESE IMPORTANT TOPICS IN PRECISION ONCOLOGY.

ASSESSMENT OF SERUM PEPTIDE PROFILING TO DETECT CANCER-SPECIFIC PATTERNS

GENETIC ANALYSIS OF MOUSE NERVOUS SYSTEM DEVELOPMENT

SIGNALING PATHWAYS THAT REGULATE SCALING AND REGENERATION OF THE CEREBELLUM

RHO GTPASE AND POLARITY SIGNALING PATHWAYS IN MORPHOGENESIS AND MIGRATION

3D STRUCTURE AND FUNCTION OF CRAC CHANNELS

SELF PEPTIDES BOUND TO MHC CLASS II IN T CELL SELECTION

STRATEGIES TO ENHANCE IMMUNE RECONSTITUTION AFTER BMT

DEFINING THE ROLE OF ERG IN MODULATING THE AR CISTROME AND ANTIANDROGEN SENSITIVITY

A RANDOMIZED TRIAL TO MINIMIZE NON-RESPONSE TO AEROBIC TRAINING IN OPERABLE BREAST CANCER

FUNCTIONAL ANALYSIS OF T2D ASSOCIATED NON-CODING SNPS

CANCER EDUCATION PROGRAM

NETWORK LEAD ACADEMIC PARTICIPATING SITE: MEMORIAL SLOAN-KETTERING CANCER CENTER

STRUCTURAL STUDIES OF RNA PROCESSING AND UBIQUITIN-LIKE PROTEIN MODIFICATION

NOVEL STRATEGIES FOR INDUCTION OF AGING IN HUMAN IPSC-DERIVED LINEAGES TOWARDS IMPROVED MODELS OF LATE-ONSET DISEASES

UNDERSTANDING PANCREATIC PROGENITORS FOR DIABETES CELL-REPLACEMENT THERAPY

MECHANISM AND REGULATION OF MEIOTIC RECOMBINATION

REGULATION OF THE INTESTINAL STEM CELL COMPARTMENT AFTER HEMATOPOIETIC TRANSPLANTATION

ONCOGENIC EVENTS IN THYROID NEOPLASIA

SYNTHESIS AND PHARMACOLOGY OF NOVEL OPIATES AND THEIR MODULATORY SYSTEMS

TARGETED ANTIGEN RECEPTOR TREATMENT OF CANCER

TOPOISOMERASES AND CHROMOSOME SEGREGATION

SANOS (SALUD Y NUTRICION PARA TODOS)

FOXO1-DEPENDENT PROGRAMME IN THE CONTROL OF REGULATORY T CELL FUNCTION

THE BREAST CANCER AND THE WORKFORCE COMMUNICATION APP: A RANDOMIZED CONTROLLED TRIAL OF AN ENGLISH/SPANISH INTERVENTION TO PROMOTE LONG-TERM JOB RETENTION

REGULATION OF Y-SECRETASE ACTIVITY BY MODULATORY PROTEINS

CHARACTERIZING THE MECHANISM OF DPP8/9 INHIBITOR-INDUCED PYROPTOSIS

CLINICAL QUALIFICATION OF IMAGING AND FLUID-BASED TUMOR MONITORING BIOMARKERS FOR METASTATIC CASTRATION RESISTANT PROSTATE CANCER

LEVERAGING FRUCTOSE TRANSPORT TO CREATE A PRIVILEGED SUBSTRATE TO SELECTIVELY FUEL T CELLS - PROJECT SUMMARY/ABSTRACT WHILE CHECKPOINT INHIBITORS AND CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS UNDERGO WIDESPREAD INVESTIGATION AS APPROACHES TO UNLEASH THE IMMUNE SYSTEM’S TUMOR-TARGETING ABILITIES, THE MECHANISMS BY WHICH THESE THERAPIES FAIL IS THE SUBJECT OF GREAT DEBATE. IN THE SETTING OF SOLID TUMORS, IT IS BELIEVED THAT THE MICROENVIRONMENT IS HOSTILE, EXCLUDING T CELLS AND/OR INHIBITING THEIR ABILITY TO PROLIFERATE OR BE ACTIVATED. A DEARTH OF METABOLIC PRECURSORS, MOST NOTABLY GLUCOSE, HAS BEEN IMPLICATED AS INHIBITING T-CELL FUNCTION. THERE REMAINS AN UNMET NEED FOR APPROACHES TO BETTER UNDERSTAND T-CELL METABOLISM AND ITS IMPACT ON TUMORS IN VIVO, AS WELL AS A METHOD TO MODULATE THIS METABOLIC LIMITATION TO OVERCOME T-CELL EXHAUSTION. GIVEN EXTENSIVE PRELIMINARY DATA, WE HAVE DEVELOPED A MODEL SYSTEM TO EXPLORE T-CELL EXHAUSTION USING PRIMARY T CELLS STIMULATED IN VITRO. WE HAVE ALSO IDENTIFIED A METABOLIC MECHANISM THAT CAN OVERCOME LIMITED GLYCOLYTIC FLUX BY UTILIZING ANOTHER BIOLOGICALLY AVAILABLE SUBSTRATE: FRUCTOSE. MOREOVER, WE HAVE OPTIMIZED METHODS TO TRACE METABOLISM IN VITRO AND IN VIVO USING HYPERPOLARIZED MAGNETIC RESONANCE (HP MR), WHICH CAN DETECT CHANGES IN METABOLISM IN REAL TIME. TAKEN TOGETHER, THESE APPROACHES PROVIDE A PLATFORM FOR STUDYING IMMUNOMETABOLISM BOTH IN 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 OF T CELLS. IN AIM 1, WE WILL EXPLORE T-CELL METABOLISM IN VIVO IN ORDER TO REVERSE THE REDUCED GLYCOLYTIC FLUX IN EXHAUSTED T CELLS. IN AIM 2, TAKING ADVANTAGE OF OUR NEWLY DEVELOPED HP FRUCTOSE, WE WILL METABOLICALLY IMAGE FRUCTOSE METABOLISM IN T CELLS USING OUR NEWLY DEVELOPED HP MICRONMR AND IN VIVO WITH HP MAGNETIC RESONANCE SPECTROSCOPIC IMAGING (MRSI). WE WILL THEN TRANSLATE THIS APPROACH TO TUMOR-BEARING MICE IN AIM 3, WHERE WE COMBINE 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 TO FURTHER OUR UNDERSTANDING OF IMMUNOMETABOLISM AND LAY THE FOUNDATION FOR FUTURE IMMUNOTHERAPY STRATEGIES IN PATIENTS.

STUDIES OF THE SMC5/SMC6 COMPLEX IN CHROMOSOMAL REPLICATION

REGULATION OF HEMATOPOIESIS BY RIBOSOMAL PROTEIN PARALOGS

EPITHELIAL OVARIAN CANCER PROGRAM PROJECT

TUMOR MICROENVIRONMENT INTERACTIONS IN BRAIN TUMORS

MORPHOGENESIS OF MAMMALIAN GUT ENDODERM

VIRAL RNA MODIFYING ENZYMES

CHARACTERIZING MSI2 IN LEUKEMIA

FLEXIBLE VERSUS STANDARD AEROBIC TRAINING DOSING IN PRIMARY BREAST CANCER: A RANDOMIZED AND RESPONSE-ADAPTED TRIAL - PROJECT SUMMARY/ABSTRACT CHEMOTHERAPY FOR PRIMARY BREAST CANCER CAUSES SIGNIFICANT DECLINES IN CARDIORESPIRATORY FITNESS (CRF) PREDISPOSING PATIENTS TO INCREASED SYMPTOM BURDEN AND INCREASED RISK OF MORBIDITY AND MORTALITY FROM CANCER AND NON-CANCER CONDITIONS. RANDOMIZED TRIALS DEMONSTRATE AEROBIC TRAINING (AT) IS FEASIBLE DURING CHEMOTHERAPY FOR PRIMARY BREAST CANCER AND ATTENUATES TREATMENT-INDUCED IMPAIRMENTS IN CRF. HOWEVER, OUR RECENT FINDINGS INDICATE THAT EVEN WITH AT DURING AND AFTER CHEMOTHERAPY, CRF REMAINS SUBSTANTIALLY BELOW NORMATIVE VALUES, AND LESS THAN 25% OF PATIENTS HAVE A CLINICALLY MEANINGFUL CRF RESPONSE. INCREASING THE DOSE OF AT SUBSTANTIALLY INCREASES CRF RESPONSE; HOWEVER, HIGHER AT DOSES ARE ASSOCIATED WITH LOWER AT ADHERENCE. THUS, USE OF A CONVENTIONAL DOSE-RESPONSE DESIGN WHEREIN PATIENTS ARE ASSIGNED TO FIXED DOSES IS LIKELY IMPRUDENT CONSIDERING LOWER FIXED AT DOSES WILL RESULT IN UNDERDOSING IN SOME PATIENTS, AND POOR ADHERENCE IN OTHERS. A MORE PATIENT- CENTERED APPROACH USED IN DRUG TRIALS IS FLEXIBLE DOSING, WHERE THE DOSE IS ESCALATED FOR EACH PATIENT AS TOLERATED. THERE HAVE BEEN NO TRIALS DIRECTLY ASSESSING THE EFFICACY OF FLEXIBLE AT DOSING ON CRF IN ANY CANCER SETTING. TO ADDRESS THIS FUNDAMENTAL KNOWLEDGE GAP IN EXERCISE-ONCOLOGY RESEARCH, THE OBJECTIVE OF THIS STUDY IS TO COMPARE THE EFFECTS OF FLEXIBLE VERSUS STANDARD FIXED AT DOSING AND RESPONSE-ADAPTED AT ON CRF RESPONSE. IN THIS RANDOMIZED TRIAL, A TOTAL OF 140 INACTIVE (<90 MINS OF MODERATE-INTENSITY EXERCISE/WK) PATIENTS WITH PRIMARY BREAST CANCER SCHEDULED TO INITIATE CHEMOTHERAPY WILL BE RANDOMLY ALLOCATED (1:1) TO FLEXIBLE DOSING: INDIVIDUAL AT DOSES ESCALATED; OR STANDARD FIXED DOSING: 90 MINS/WEEK FOR ~32 WEEKS (DURING AND AFTER CHEMOTHERAPY). PATIENTS WHO DO NOT RESPOND (<3.50 ML/KG/MIN CRF IMPROVEMENT) AT 32 WEEKS WILL COMPLETE 20 WEEKS OF EXTENDED FLEXIBLE DOSING AT. WE WILL ADDRESS 3 SPECIFIC AIMS: AIM 1: COMPARE THE EFFECTS OF FLEXIBLE VERSUS STANDARD DOSING ON CRF RESPONSE RATE. AIM 2: ASCERTAIN THE EFFECTS ON ADHERENCE, SAFETY, AND PATIENT-REPORTED OUTCOMES. AIM 3: EVALUATE THE EFFECTS OF EXTENDED AT IN CRF NON-RESPONDERS. IMPACT: THIS STUDY CHALLENGES THE CURRENT DOGMA THAT ALL PATIENTS RESPOND EQUALLY TO A FIXED AT DOSE AND WILL BE THE FIRST TO EVALUATE FLEXIBLE AT DOSING IN ANY CANCER POPULATION. RECEIVING CANCER TREATMENT IS NOT A QUALIFYING CONDITION FOR STRUCTURED AT AND, AS SUCH, AT IS NOT CURRENTLY CONSIDERED A STANDARD ASPECT OF CANCER MANAGEMENT. WE ANTICIPATE THE PROPOSED TRIAL WILL DIRECTLY ADDRESS AN UNMET CLINICAL NEED BY IDENTIFYING THE AT REGIMEN THAT MAXIMIZES CRF RESPONSE RATE AND, IF SUCCESSFUL, FINDINGS FROM THIS INVESTIGATION WILL HELP GUIDE THE AT REGIMEN FOR TRANSLATION TO CLINICAL CARE.

THE FRAMINGHAM SCHOOL NEVUS STUDY

FERROPTOSIS, CELLULAR METABOLISM, AND CANCER

SINGLE CELL MAPPING OF DEVELOPMENTAL TRAJECTORIES UNDERLYING HEALTH AND DISEASE

CC-CHEMOKINES IN LISTERIA INFECTION.

INFLUENCE TRIAL: IMPROVING EVENT-FREE SURVIVAL BY OPTIMIZING FLUDARABINE EXPOSURE DURING LYMPHODEPLETION FOR CAR T CELL THERAPY

SCREENING COLONOSCOPY FEASIBILITY TRIAL

OBESITY, CHEMOTHERAPY DOSING, AND BREAST CANCER OUTCOMES

THE ROLE OF P21-ACTIVATED KINASES IN MALIGNANT MESOTHELIOMA

CLINICAL SCHOLARS BIOMEDICAL RESEARCH TRAINING PROGRAM

TARGETING MASTER REGULATORS OF THE BREAST CANCER METASTASIS TRANSCRIPTOME

INTEGRATION OF RETROVIRAL DNA: ACCESSING HOST TARGET DNA

TARGETING ONCOGENIC RAS-MAPK SIGNALING COMPLEXES VIA THE SCAFFOLD KSR

COMPARATIVE EFFECTIVENESS OF ACUPUNCTURE FOR CHRONIC PAIN AND CO-MORBID CONDITIONS IN VETERANS

MECHANISMS AND FUNCTION OF AUTOPHAGY IN CANCER

STRUCTURE AND FUNCTION OF INTEGRASE

MECHANISMS CONTROLLING EPITHELIAL HOMEOSTASIS

MECHANISM OF DNA REPLICATION INITIATION IN SACCHAROMYCES CEREVISIAE

P21-ACTIVATED KINASES AS NEW THERAPEUTIC TARGETS IN NEUROFIBROMATOSIS TYPE 1

IMMIGRANT ENCLAVES: CONFERRING HEALTH ADVANTAGES OR CREATING HEALTH DISPARITIES IN CHINESE IMMIGRANTS?

ISOLATION OF NOVEL MUTATIONS AFFECTING THE MOUSE EMBRYO

ADOPTIVE IMMUNOTHERAPY OF CANCER WITH IL-12 SECRETING TUMOR-TARGETED T CELLS

TRANSCRIPTIONAL CONTROL OF NK CELL METABOLISM - PROJECT SUMMARY NATURAL KILLER (NK) CELLS COMPRISE AN IMPORTANT ARM OF THE HOST INNATE IMMUNE SYSTEM THAT DETECTS AND ELIMINATES VIRUS-INFECTED CELLS. NEWBORNS AND IMMUNE-COMPROMISED PATIENTS LACKING NK CELLS ARE EXTREMELY SUSCEPTIBLE TO VIRAL INFECTION. IN PARTICULAR, HUMAN CYTOMEGALOVIRUS (HCMV) CAN CAUSE SEVERE HEALTH COMPLICATIONS OR BE LIFE-THREATENING IN THESE INDIVIDUALS. MOUSE CYTOMEGALOVIRUS (MCMV) IS AN ACCURATE AND ROBUST MODEL FOR INVESTIGATING NK CELL RESPONSES AGAINST HCMV. USING MCMV INFECTION IN MICE, WE HAVE DISCOVERED THAT NK CELLS POSSESS NOVEL ADAPTIVE IMMUNE FEATURES SUCH AS CLONAL EXPANSION AND LONG-LIVED MEMORY. IN THE PAST DECADE, OUR LABORATORY HAS UNCOVERED MANY OF THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING NK CELL MEMORY. OUR LONG-TERM GOALS ARE TO UNDERSTAND THE GENERAL BIOLOGY OF NK CELLS, AND THE MOLECULAR BASIS BY WHICH THESE POWERFUL INNATE LYMPHOCYTES CAN MEDIATE PROTECTION AGAINST PATHOGEN INVASION. TO THIS END, WE HAVE RECENTLY IDENTIFIED SEVERAL TRANSCRIPTIONAL AND METABOLIC PATHWAYS THAT MAY INFLUENCE THE NK CELL RESPONSE AGAINST MCMV INFECTION. BASED ON THIS EXCITING PRELIMINARY DATA, OUR CURRENT R01 GRANT PROPOSES TO USE CUTTING EDGE METABOLOMICS AND NEWLY ENGINEERED TRANSGENIC MOUSE MODELS TO STUDY HOW METABOLISM IN ANTIVIRAL NK CELLS IN TRANSCRIPTIONALLY REGULATED. IN AIM 1, WE SEEK TO UNDERSTAND HOW PROINFLAMMATORY CYTOKINES AND THE STAT FAMILY OF TRANSCRIPTION FACTORS CONTROL OF NK CELL METABOLISM DURING MCMV INFECTION. IN AIM 2, WE WILL DETERMINE THE REQUIREMENT FOR AEROBIC GLYCOLYSIS AND FATTY ACID OXIDATION IN ANTIVIRAL NK CELLS USING CONDITIONAL ABLATION OF GENES ENCODING LDHA AND CPT1A, RESPECTIVELY. IN AIM 3, WE WILL DETERMINE WHETHER THE TRANSCRIPTION FACTOR BHLHE40 REGULATES MITOCHONDRIAL METABOLISM AND FITNESS IN EFFECTOR NK CELLS FIGHTING MCMV INFECTION. ALTOGETHER, THE STUDIES IN THIS R01 PROPOSAL WILL GREATLY INCREASE OUR UNDERSTANDING OF THE UNDERLYING TRANSCRIPTIONAL AND METABOLIC MECHANISMS WHEREBY NK CELLS CONTRIBUTE TO HOST DEFENSE DURING VIRAL INFECTION, AND ESTABLISH NOVEL TRANSLATIONAL PARADIGMS FOR HARNESSING THE NK CELL COMPARTMENT FOR IMMUNIZATION AND THERAPEUTIC STRATEGIES AGAINST INFECTIOUS DISEASES.

THE ROLE OF ENTOSIS IN HUMAN CANCERS

INDIVIDUAL MEANING-CENTERED PSYCHOTHERAPY IN ADVANCED CANCER PATIENTS

MOLECULAR CONTROL OF TISSUE MORPHOGENESIS

OPTIMIZING TOBACCO TREATMENT FOR SMOKERS SEEKING LUNG CANCER SCREENING

STRUCTURAL STUDY OF EPH RECEPTORS AND EPHRINS

INVESTIGATING THE FUNCTIONS OF THE MIR-17~92 FAMILY OF ONCOGENIC MICRORNA CLUSTER

IDENTIFYING AND TARGETING METABOLIC DEPENDENCIES IN THE PANCREATIC TUMOR MICROENVIRONMENT