Targeting chromatin remodeling complex controlled fusion protein function in rhabdosarcoma
Mentor Name: Jun Qi
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 the important fusion protein can block 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 functions of the BPTF-controlled fusion protein drive cancer progression and develop a novel therapeutic strategy for this aggressive RMS subtype.
