Targeting mutant-MYOD1 driven rhabdomyosarcoma - PROJECT SUMMARY Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in the pediatric population. A lethal form of this tumor is driven from MYOD1 mutations occurring in conserved residues in the DNA binding domain. These soft tissue sarcomas are almost universally lethal, frequently metastasize, rapidly progress, do not respond well to standard therapy, and are an unmet medical need. Identifying effective treatments for these tumors is critical, as are correlative or “reverse translational” studies to identify tumor-driving mechanisms. The primary goal of this application is to establish a robust preclinical/clinical pipeline (bench-to-bedside and back) to rapidly develop and test new therapies for this deadly malignancy. Our effort will harness the specialized expertise of both clinical investigators at the NCI and extramural experts in RMS biology and translational epigenetics, and will leverage the unique resources of the NIH Clinical Center. Our project builds upon strong preliminary and published genomics and functional data from our team, suggesting that PI3K is a unique vulnerability in MYOD1-mutant RMS. These insights will be used to develop rational single agent and combination therapies and will be tested in robust preclinical RMS models. These insights will then be used to perform clinical trials in RMS patients with an emphasis on correlative studies to understand the precise genetic contexts where the clinical agents are effective therapy within the same trial within the Intramural NIH Clinical Center. This will allow for more timely identification of active agents and will allow patients to have more treatment options available to them. The preclinical to clinical translation will be complemented by comprehensive genomic analyses of tumor samples obtained prior to treatment and on treatment with novel agents to identify mechanisms of response and resistance to therapy. Insight and samples from clinical trial participants will serve as the foundation for correlative studies, including single cell multi-omics and cell-free DNA analysis, to understand therapy-resistance and develop improved therapies. Our project also addresses fundamental questions in cancer etiology. We have exciting preliminary data revealing that MYOD1-mutant RMS tumors are dependent upon PI3K activity and have unique epigenetic reprogramming. Our extramural basic science team will integrate highly innovative technologies to understand how and why chromatin structural alterations and PI3K can together drive oncogenesis. Thus, the project’s broad long-term objectives are to address an unmet medical need and provide mechanistic insight that will reveal new vulnerabilities and clinical development. We have assembled a multi- disciplinary team of basic and clinical scientists to develop and translate promising therapies for individuals with MYOD1-mutant RMS. This project will allow more effective and rapid translation of promising new therapies for RMS and will expand the type of therapies that are developed. These studies have the potential to develop a new standard of care for patients with MYOD1-mutant RMS.
