Vulnerabilities in the Transcriptional Program of Fusion-Positive Rhabdomyosarcoma
Abstract
Project Overview: Many sarcomas are driven by chromosomal translocations, where a segment from one chromosome is swapped with a segment of a different chromosome, resulting in new genetic code called a ‘fusion oncogene’. Some of the fusion oncogenes encode transcription factors, which are especially challenging to target as they are intrinsically disordered and lack drug-binding sites. These difficulties are exemplified by fusion- positive rhabdomyosarcoma, which is driven by the fusion oncogene PAX3-FOXO1 and remains among the most difficult to treat cancers in children and young adults. PAX3-FOXO1 disrupts normal DNA organization and regulation and also amplifies the transcription of pro-tumorigenic genes. In addition, PAX3-FOXO1 may contribute to therapy resistance by dysregulating normal cell cycle checkpoints. Radiation and cytotoxic chemotherapy causes DNA damage. Ordinarily, DNA-damaged cells would not be permitted to continue to transit the cell cycle. However, gene dysregulation caused by PAX3-FOXO1 allows the cell to progress through these checkpoints despite DNA damage. Unfortunately, attempts to directly target PAX3-FOXO1 have proven futile as it lacks good drug-binding pockets. Although PAX3-FOXO1 is currently unable to be targeted directly, our work seeks to identify proteins that collaborate with PAX3-FOXO1 – co-activators – that could be exploited for therapy. We discovered co- activators that are able to regulate the activity of PAX3-FOXO1 and also are key regulators of the cell cycle in fusion-positive rhabdomyosarcoma. This project investigates how these co-activators, which can be targeted therapeutically, may be tractable vulnerabilities to PAX3-FOXO1 transcriptional programs. The goals of this proposal are to investigate mechanisms by which PAX3-FOXO1 activity is dependent on these co-activators and to use a small molecule inhibitor to exploit this dependency in our preclinical models. Using a functional genomics screen, we will also discover and investigate new druggable co-activators that are dependencies for the expression and activity of PAX3-FOXO1. Ultimately, we hope our work will inform the development of new therapeutic approaches for treating patients with fusion-positive rhabdomyosarcoma. PI Career Goals: My career goal is to become an independent scientist leading a laboratory focused on identifying new and better ways to target the transcriptional programs orchestrated by fusion oncogenes responsible for many sarcomas. Despite numerous advances in the treatment of pediatric and adult malignancies, oncoprotein-driven sarcomas remain among the most difficult to treat tumors. These challenges are exemplified in fusion-positive rhabdomyosarcoma, which is the most common soft tissue sarcoma in adolescents and young adults. In fact, the first-line chemotherapy regimen for these tumors has not changed over the past 4 decades. Inspired by many adolescent patients who bravely battled metastatic sarcomas, I have committed my career to investigating new treatment strategies. This research addresses two of the Fiscal Year 2022 (FY22) European Paediatric Soft Tissue Sarcoma Study Group (PRCRP) Topic Areas: (1) sarcoma and (2) pediatric, adolescent, and young adult cancers; and it is focused on advancing two of the Therapeutics-related FY22 PRCRP overarching challenges: (1) identifying new targets for a cancer frequently associated with advanced/metastatic disease, and (2) identifying and elucidating mechanisms behind cancer epigenetics to improve treatment methods. Although PAX3-FOXO1 has been unable to be targeted directly, my proposal seeks to identify and exploit its reliance on co-activators and for its transcriptional programming. Executing the Aims of this proposal and my career development plan will provide me with deep expertise in molecular oncology, chromatin biology, and sarcoma preclinical modeling. The data generated will also provide a foundation for numerous fu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310228
Entities
People
- Michael Deel
Organizations
- Duke University
- United States Army