“Spirit of Jimmy V” Award funded by the Dick Vitale Gala in honor of Holly Rowe
Fusion-positive rhabdomyosarcoma is driven by a specific fusion gene called PAX3-FOXO1 that acts as a powerful cancer driver. Unfortunately, this fusion gene is not yet able to be targeted directly with drugs. In fact, clinical trials over the past several decades have failed to improve the 5-yr overall survival rate for patients with fusion-positive rhabdomyosarcoma, which remains <50% for all-comers and <10% when metastatic. Prior work from our laboratory revealed that the Hippo pathway, a signaling network that in development ordinarily regulates the growth of organs and tissues, is turned off by PAX3-FOXO1. With Hippo turned off, pro-growth signals are left unchecked and cells become stimulated to proliferative. One of the main signals that gets activated by silencing of Hippo is TAZ, which is a powerful co-activator of cancer-promoting genes. We have seen that TAZ promotes resistance to chemotherapy and regulates the rhabdomyosarcoma cancer stem cell population. Our current studies, which utilize a variety of molecular biology and biochemical approaches in several cell culture and mouse model systems, aim to determine mechanisms by which TAZ controls chemoresistance and stemness. Ultimately, we are seeking to find vulnerabilities within the TAZ/PAX3-FOXO1 axis that can be exploited as novel therapies.