Targeting Chromatin Remodeling Complexes for Rhabdomyosarcoma (RMS) Therapy
Rhabdomyosarcoma (RMS) is a pediatric tumor reminiscent of immature skeletal muscle. The most aggressive subtype contains gene fusions between PAX3/7 and FOXO1 (termed fusion protein RMS or FP-RMS), which predict poor 5-year survival rates approximated at 20-30% that have not significantly improved in several decades. Therapy for the aggressive RMS subtype relies upon surgery, radiation, and toxic drugs including vincristine (targeting microtubules and inhibiting mitosis), actinomycin (non-specific inhibitor of gene expression), and cyclophosphamide (crosslinking DNA). These treatment options do not guarantee long-term disease-free survival and are often harsh, significantly hurting the quality of life for these young patients. Thus, there is a critical unmet need to develop a more targeted precision medicine approach for treating these aggressive pediatric tumors. To this effort, we identified a novel target, bromodomain PHD-finger transcription factor (BPTF) as a dependency specific to FP-RMS. BPTF directly interacts with and controls the key oncogene in FP-RMS, and is important for FP-RMS cells. We have utilized a chemical biology approach and developed a small molecule degrader that can effectively eliminate BPTF and interrupt fusion protein function in cells. This direct impact on this important fusion protein can block the FP-RMS cell growth in cell culture and in our animal model. Utilizing our novel chemical tool compounds, we aim to understand the key mechanism by which the BPTF controlled the fusion protein functions drive cancer progression and develop a novel therapeutic strategy for this aggressive RMS subtype.
In this study, we aim to achieve two goals: 1) to develop novel therapeutic agents that selectively and specifically eliminate BPTF, a protein that regulate key fusion protein in the most lethal type of rhabdomyosarcoma, PAX3-FOXO1 fusion positive RMS (FP-RMS); 2) the use our novel agents to functionally interrogate dissect the key mechanism of PAX3-FOXO1 functions regulated by BPTF. Our study will build a pre-clinical rationale for develop a novel therapeutic strategy for FP-RMS.