Chemical approaches to modulate PAX3-FOXO1 in fusion-positive alveolar rhabdomyosarcoma

Active Cooperative Agreement Awarded Last action

Award ID
UM1CA294108
Recipient
Awarding agency
Obligated
$11,458,719

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date 43% complete
Place of performance
Cambridge, MA 02139, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $2,262,989
Amendment $0
Amendment $0
Amendment $2,271,313
Amendment $2,271,313
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Amendment $2,326,552
Original award $2,326,552
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Subawards

Subrecipient Amount Awarded
Duke University Generate preclinical data to plan prioritizing development of novel pharmacological agents into therapies against Fusion-Positive Rhabdomyosarcoma. $302,683
The Regents Of The University Of California Identify covalent degraders in cancer cells. $880,282
The Broad Institute, Inc. Provide executive Committee members for project leadership and leaders within project's individual working groups. $1,558,208

Quick answers

Who received award UM1CA294108?

UM1CA294108 was awarded to Massachusetts Institute Of Technology by National Cancer Institute (National Institutes of Health) on September 6, 2024.

How much is award UM1CA294108 worth?

$11,458,719 has been obligated on UM1CA294108.

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