Project Grant F31CA290924
- This Project Grant award from the National Cancer Institute (CFDA 93.398 - Cancer Research Manpower) provides $290,017.00 to St. Jude Children's Research Hospital Inc. to investigate the cell state hierarchy and transcriptional/epigenetic determinants of therapy-resistant progenitor-like cells in fusion-negative rhabdomyosarcoma (FN-RMS), a type of pediatric soft tissue sarcoma. The award will support computational and experimental research approaches, including single-cell RNA sequencing,...
- This $156,136 Project Grant award from the National Center for Advancing Translational Sciences (NCATS), CFDA 93.350, aims to develop biochemical reagents and assays to analyze the structure and function of the PAX3-FOXO1 fusion protein that drives the rare disease alveolar rhabdomyosarcoma. Specifically, the project will generate recombinant PAX3-FOXO1 constructs and conduct preliminary structural screening using innovative nuclear magnetic resonance techniques. It will also establish in...
- This Cooperative Agreement award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $481,052 to the Research Institute at Nationwide Children's Hospital to develop a preclinical/clinical pipeline to rapidly test new therapies for a deadly form of pediatric rhabdomyosarcoma (RMS) driven by mutant MYOD1. The primary goal is to identify effective treatments, including PI3K-targeted therapies, for this almost universally lethal malignancy by leveraging...
- This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $194,013 to Sanford Research, a non-profit biomedical research organization, to develop the first genetically engineered mouse models that accurately replicate key features of human high-risk rhabdomyosarcoma. The goal is to use these advanced preclinical models to explore the role of the NOTCH1 signaling pathway as both a driver and potential therapeutic target for this aggressive form...
- This federal Project Grant award from the Department of Health and Human Services National Institutes of Health National Cancer Institute, under the Cancer Cause and Prevention Research program (CFDA 93.393), provides $613,054 to St. Jude Children's Research Hospital Inc. to study the mechanisms by which transcription factors control different cell states in neuroblastoma, a high-risk pediatric tumor. The key objectives are to 1) interrogate how master transcription factors control the...
- This Project Grant award, valued at $611,591.00 and provided by the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) federal grant program, aims to research new strategies to overcome therapy resistance in Hedgehog pathway-driven medulloblastoma, the most common malignant pediatric brain cancer. The key focus areas of this research project include: 1) investigating a new...
- This Project Grant award from the National Cancer Institute's Cancer Research Manpower program (CFDA 93.398) provides $151,040 in funding to St. Jude Children's Research Hospital Inc. to elucidate the role of an essential transcription factor in SWI/SNF-mutant rhabdoid tumors. The research aims to characterize the function of this poorly understood transcription factor and its interaction with a repressive chromatin-regulatory complex in the unique cellular environment resulting from the loss of...
- This federal Project Grant award from the National Cancer Institute (CFDA 93.396 - Cancer Biology Research) supports research at the University of Houston System to investigate the role of the TAK1 signaling protein in the development and growth of rhabdomyosarcoma, a type of cancerous sarcoma. The $658,223 award, running from February 1, 2025 to January 31, 2030, will fund studies to examine the molecular mechanisms by which TAK1 drives rhabdomyosarcoma tumorigenesis and inhibits myogenic...
- This Project Grant award of $143,788 from the National Cancer Institute's Cancer Research Manpower program (CFDA 93.398) supports research on genetic dependencies in pediatric low-grade gliomas (PLGG) with KIAA1549-BRAF rearrangements. The primary goals are to understand how the KIAA1549:BRAF fusion is activated, and why the POMT complex is essential for the survival of KIAA1549:BRAF-dependent cells. The research will test hypotheses related to the role of POMT enzymatic activity,...
- This Project Grant award from the National Cancer Institute (CFDA 93.398 Cancer Research Manpower) provides $167,584.00 to the University of California, San Diego (UCSD) to generate human induced pluripotent stem cell (hiPSC) models of atypical teratoid rhabdoid tumors (ATRTs) - an aggressive form of pediatric brain cancer. The primary goals are to investigate the cell of origin for ATRTs and identify potential therapeutic vulnerabilities. Specifically, the award supports research to derive...
DETERMINING THE MECHANISM OF RHABDOMYOSARCOMA TRANSFORMATION FROM A NON-MYOGENIC CELL OF ORIGIN - PROJECT SUMMARY/ABSTRACT RHABDOMYOSARCOMA (RMS) IS AN AGGRESSIVE SOLID TUMOR AND THE MOST COMMON PEDIATRIC SOFT TISSUE SARCOMA. RMS TREATMENT CONSISTS OF CHEMOTHERAPY, RADIATION, AND SURGERY WITH NO FDA APPROVED TARGETED THERAPIES TO DATE. DESPITE DECADES OF RESEARCH AND CLINICAL TRIALS, HIGH RISK PATIENTS FACE AN OVERALL SURVIVAL RATE OF LESS THAN 30%. FUSION-NEGATIVE RMS (FN-RMS), THE MOST COMMON SUBTYPE, IS GENETICALLY HETEROGENEOUS WITH CELLS RESEMBLING AN ARRESTED STATE OF SKELETAL MUSCLE DIFFERENTIATION. FN-RMS CAN ARISE ANYWHERE IN THE BODY BUT PREDOMINATELY DEVELOPS IN THE HEAD AND NECK. TUMORS COMMONLY DEVELOP IN REGIONS COMPLETELY DEVOID OF SKELETAL MUSCLE SUCH AS THE URINARY BLADDER, PROSTATE, AND BILIARY TREE. THIS CHALLENGES THE LONG-HELD CONCEPTION THAT RMS ORIGINATES FROM A SKELETAL MUSCLE PROGENITOR THAT ESCAPES TERMINAL MUSCLE DIFFERENTIATION. HOWEVER, IT IS CURRENTLY UNKNOWN HOW A NON-MYOGENIC PROGENITOR UNDERGOES MYOGENIC TRANSFORMATION IN FN-RMS. THE OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THE MECHANISM OF FN-RMS TRANSFORMATION FROM A NON-MYOGENIC CELL OF ORIGIN. THIS WILL ALSO IDENTIFY THE CRITICAL DETERMINANTS OF RMS CELL FATE WHICH HAVE YET TO BE ELUCIDATED. THE OVERALL HYPOTHESIS OF THIS PROPOSAL IS THAT RMS TRANSFORMATION FROM A NON-MYOGENIC CELL OF ORIGIN REQUIRES ACCESS TO AND EXPRESSION OF LINEAGE SPECIFICATION FACTORS UPSTREAM OF MYOGENIC REGULATORY FACTORS SUCH AS MYOD1 AND MYF5. I WILL ADDRESS THIS HYPOTHESIS WITH THE FOLLOWING SPECIFIC AIMS: (1) DEFINE CHROMATIN LANDSCAPE CHANGES DURING FN-RMS TRANSFORMATION, AND (2) DETERMINE THE TRANSCRIPTION FACTORS (TFS) REQUIRED FOR RHABDOMYOSARCOMAGENESIS. WE CHARACTERIZED A MOUSE MODEL OF FN-RMS ARISING FROM A NON-MYOGENIC CELL OF ORIGIN WHERE CRE-RECOMBINATION DRIVEN BY THE ADIPOSE PROTEIN 2 (AP2) PROMOTER ACTIVATES ONCOGENIC SONIC HEDGEHOG (SMOM2) SIGNALING (AP2-CRE;R26SMOM2). THESE TUMORS ARISE EXCLUSIVELY IN THE HEAD AND NECK AND RESEMBLE FN-RMS PATIENT TUMORS BY HISTOLOGY AND GENE EXPRESSION PROFILES. USING THIS MODEL, I WILL ASSESS HOW CHROMATIN ACCESSIBILITY, EPIGENETIC MARKS, AND INTERACTIONS ARE ALTERED UPON MYOGENIC TRANSFORMATION. I WILL THEN USE A COMBINATION OF CONDITIONAL KNOCKOUT MOUSE MODELS AND AN IN VITRO DIRECTED DIFFERENTIATION CRISPR SCREEN TO DETERMINE THE RMS-ASSOCIATED TFS REQUIRED FOR TRANSFORMATION. TO IMPROVE CLINICAL OUTCOMES, A BETTER UNDERSTANDING OF THE BIOLOGY DRIVING RMS IS CRITICAL. THIS PROJECT WILL PROVIDE NOVEL INSIGHTS INTO THE KEY MECHANISTIC DETERMINANTS OF FN-RMS CELL FATE ALLOWING FOR MYOGENIC TUMORS TO ARISE IN SITES COMPLETELY DEVOID OF SKELETAL MUSCLE. THE CRITICAL DRIVERS OF RMS CELL FATE CAN THEN BE LEVERAGED TO GENERATE NEW TARGETED THERAPIES.
Mod # | Description | ReasonForModification | Federal Obligation | Date |
|---|---|---|---|---|
| Not listed | $0 | 5/28/25 | ||
| Not listed | $564 | 5/28/25 | ||
| Not listed | $564 | 5/28/25 | ||
| Not listed | $48.0k | 5/13/25 | ||
| Not listed | $48.0k | 5/13/25 |