P01CA298963

FUSION ONCOPROTEIN CONDENSATES IN PEDIATRIC CANCERS - PROJECT SUMMARY - OVERALL FUSION ONCOPROTEINS (FOS), ARISING FROM GENE TRANSLOCATIONS, GIVE RISE TO ~17% OF ALL CANCERS. NOTABLY, FOS ARE COMMONLY ONCOGENIC DRIVERS IN PEDIATRIC CANCERS, INCLUDING MANY WITH POOR PROGNOSIS. THE FUSONC PROGRAM PROJECT SYNERGISTICALLY ASSEMBLES LEADING BASIC AND TRANSLATIONAL SCIENTISTS TO COLLABORATIVELY STUDY FOS SEEN IN PEDIATRIC CANCERS, INCLUDING ACUTE LYMPHOBLASTIC AND MYELOID LEUKEMIAS (ALL & AML, MULLIGHAN & KLCO), EPENDYMOMA (EPN, MACK) AND MESENCHYMAL CHONDROSARCOMA (MCS, WANG). MANY FOS PROMOTE ONCOGENESIS BY DRIVING ABERRANT GENE EXPRESSION. RECENTLY, FUSONC INVESTIGATORS SHOWED THAT FOS DEREGULATE GENE EXPRESSION BY FORMING ABERRANT NUCLEAR BIOMOLECULAR CONDENSATES. BIOMOLECULAR CONDENSATES ARE MEMBRANELESS, MESO-SCALE ASSEMBLIES THAT MEDIATE DIVERSE BIOLOGICAL PROCESSES IN HEALTHY CELLS, INCLUDING REGULATION OF GENE EXPRESSION. FUSONC RESEARCHERS HAVE SHOWN THAT SEVERAL FOS FORM ABERRANT CONDENSATES THAT DEREGULATE GENE EXPRESSION—SO-CALLED “ONCO-CONDENSATES”. EXAMPLES INCLUDE: NUP98 AND NUTM1 FOS IN ACUTE LEUKEMIA, ZFTA:RELA IN EPENDYMOMA, AND HEY1::NCOA2 IN MESENCHYMAL CHONDROSARCOMA. HOWEVER, DESPITE THESE ADVANCES, FUTURE STUDIES ARE NEEDED TO ADDRESS THE FOLLOWING QUESTIONS: (1) DO FOS GENERALLY DRIVE ONCOGENESIS THROUGH CONDENSATE FORMATION ACROSS THE DIVERSE LANDSCAPE OF PEDIATRIC CANCER? AND (2) WILL GAINING THIS MECHANISTIC KNOWLEDGE PROPEL THE DEVELOPMENT OF NOVEL FO-TARGETED THERAPIES? THE FUSONC PROGRAM PROJECT ASSEMBLES EXPERTS IN CONDENSATE BIOPHYSICS (KRIWACKI, PROJECT 1), MCS (WANG, PROJECT 1), PEDIATRIC ALL AND AML (MULLIGHAN & KLCO, PROJECT 2), EPN (MACK, PROJECT 3), BIOSTATISTICS (POUNDS, CORE 1), CRISPR TILING-BASED FUNCTIONAL ANALYSES OF FOS (CHEN, CORE 2) AND OPTOGENETIC INDUCTION OF FO CONDENSATES (XU, CORE 3) TO ADDRESS THE QUESTIONS ABOVE BY ACCOMPLISHING FOUR OVERARCHING GOALS. GOAL 1 WILL ELUCIDATE THE BIOPHYSICAL MECHANISMS UNDERLYING CONDENSATE FORMATION BY FOS. GOAL 2 WILL DISCOVER HOW FOS DEREGULATE GENE EXPRESSION, ALTER CHROMATIN LANDSCAPES, AND PROMOTE ONCOGENESIS. GOAL 3 WILL IDENTIFY THE PROTEIN INTERACTION PARTNERS OF FOS AND THE UNDERLYING MECHANISMS OF THEIR INTERACTIONS. AND GOAL 4 WILL REVEAL POTENTIAL THERAPEUTIC TARGETS FOR TREATMENT OF FO-DRIVEN PEDIATRIC CANCERS. THESE GOALS WILL BE ACCOMPLISHED THROUGH MULTIPLE COLLABORATIVE INTERACTIONS AND SYNERGIES BETWEEN PROJECTS AND CORES INVOLVING, THE EXCHANGE OF REAGENTS, SHARING OF DATA ANALYSIS PLATFORMS, DISSEMINATION OF STATISTICAL EXPERTISE, PROVISION OF SEVERAL ADVANCED TECHNICAL PLATFORMS, SHARING OF TECHNICAL EXPERTISE, AND THE DEVELOPMENT AND SHARING OF CELLULAR AND IN VIVO CANCER MODEL SYSTEMS. WE STRONGLY ARGUE THAT THE FUSONC PROGRAM PROJECT WILL REVOLUTIONIZE OUR MECHANISTIC UNDERSTANDING OF SEVERAL HIGH-RISK, FO-DRIVEN PEDIATRIC CANCERS AND PROPEL THE DEVELOPMENT OF MECHANISM-BASED TARGETED THERAPIES AGAINST THESE CANCERS.

St. Jude Children's Research Hospital

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Memphis, Tennessee 38105 United States

Single Zip Code

National Cancer Institute Program Project Applications for the Years 2023, 2024, and 2025 (P01 Clinical Trial Optional) (PAR-23-059)