Funded by the Dick Vitale Pediatric Cancer Research Fund
Rhabdomyosarcoma (RMS) is a connective tissue cancer with features of skeletal muscle, and the most common soft tissue cancer of childhood. RMS can be classified as lacking or having a PAX3::FOXO1 fusion, in which part of the PAX3 protein becomes attached to part of the FOXO1 protein. This hybrid, fused protein is the driving mutation of fusion-positive RMS (FP-RMS). Survival for children with FP-RMS is less than 30%, and this has not improved in over 40 years. In fact, we have no new effective drugs for this cancer. Chemotherapies developed in the 1970s are still the best we have today. This research focuses on understanding how to block PAX3::FOXO1. However, PAX3::FOXO1 is a difficult drug target due to its complex structure. To complicate matters, at least six other fusions have recently been discovered that drive FP-RMS. Rather than being discouraged, we have leveraged this information. We have figured out that all of these seven fusions depend upon a core set of helper proteins to cause FP-RMS. In this project we will figure out the regions of the seven fusions that have common roles and that are responsible for recruiting the helper proteins. Last, we will use hi-tech chemistry to find small molecules to attach to these common regions to dissolve away the helper proteins. This will provide a platform from which to design, and in the future, clinically evaluate new drugs to block any fusion found in FP-RMS. We hope to provide targeted, less toxic treatments.
