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Chemical Approaches to Modulate PAX3-FOXO1 in Fusion-Positive Alveolar Rhabdomyosarcoma

Award Number: UM1CA294108
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/06/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Chemical Approaches to Modulate PAX3-FOXO1 in Fusion-Positive Alveolar Rhabdomyosarcoma - PROJECT SUMMARY/ABSTRACT Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) remains a poorly understood but highly fatal cancer of childhood. The pathognomonic fusion oncoprotein of ARMS is PAX3-FOXO1 (i.e., PAX3::FOXO1, P3F), a transcription factor fusion driving ARMS progression through dysregulation of gene expression and chromatin state. Major obstacles to the development of therapies for FP-RMS and other oncogenic fusion proteins include the high degree of conformational plasticity of the fusion protein drivers and the lack of knowledge about protein partners or suitable mechanisms for inhibiting or clearing the fusions. To solve these gaps, we need a comprehensive, coordinated approach to discover and develop chemical agents that clarify the relevance of various molecular mechanisms capable of inhibiting PAX3-FOXO1-mediated tumorigenesis. We assembled a team of chemical biologists, medicinal chemists and RMS-focused physician-scientists whose unique and complementary expertise in high-throughput screening, chemoproteomics, quantitative molecular interaction analyses, transcriptional biology, medicinal chemistry, pharmacology and RMS biology will be applied to the discovery and development of small molecules that impact PAX3-FOXO1 function in FP-RMS. A key goal of the Center is to explore multiple mechanisms of action for targeting PAX3-FOXO1 and efforts will emphasize 1) identifying direct small-molecule binders of PAX3-FOXO1 or nearest neighbor proteins that may be pursued as direct functional modulators or silent binders for degrader development, 2) development of PAX3-FOXO1 degraders, including heterobifunctional proteolysis targeting chimeras (PROTACs) and molecular glues that degrade a target by hijacking the ubiquitin-proteasome system, and 3) indirect targeting of PAX3-FOXO1 by targeting transcriptional network collaborators that modulate the function of the fusion or that control transcription of the fusion. We propose three complementary Projects supported by four Research Groups, including the High-Throughput Screening Group (HTS), the Molecular & Cellular Mechanism Group (MCM), the Medicinal Chemistry Group (Med Chem), and the Pharmacology Group (Pharm). The Specific Aims involve all four Research Groups and include: 1) Ligand Discovery for PAX3-FOXO1 (Project 1); 2. Discovery and Development of Targeted Protein Degraders for PAX3-FOXO1 (Project 2); and 3. Targeting the PAX3-FOXO1-associated core regulatory transcriptional complex (Project 3). While the aims to explore multiple pharmacologic modes of perturbing PAX3-FOXO1 activities are ambitious, our combined expertise and experience in balancing foraging and focusing in drug discovery or development will enable our goal of accelerating the identification of therapies for PAX3-FOXO1-positive FP-RMS. Our unique strengths will also inform the TFCC Network, resulting in knowledge generalizable to targeting of fusion oncoproteins in childhood cancer and accelerating advances in clinical care.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	2	4/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $2,271,313 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	2	8/28/2025	NON-COMPETING CONTINUATION	$2,271,313
2025	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	1	12/17/2024	NEW	$0
														Subtotal = $2,271,313

Issue Date FY: 2024 ( Subtotal = $2,326,552 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	1	9/6/2024	NEW	$2,326,552
														Subtotal = $2,326,552

Grand Total All Awards = $4,597,865

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Chemical Approaches to Modulate PAX3-FOXO1 in Fusion-Positive Alveolar Rhabdomyosarcoma

Award Number: UM1CA294108

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/06/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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