A Novel and Rationale Drug Combination in Preclinical Models of Rhabdomyosarcoma
Mentor Name: Michael Deel
Rhabdomyosarcoma, the most common soft tissue cancer in children and adolescents, remains a difficult tumor to cure. In fact, the 5-year overall survival rates for high-risk metastatic rhabdomyosarcoma remain below 30% and have not significantly improved over the past several decades. Prior work from our laboratory and others have demonstrated that transcriptional co-activators YAP1 and TAZ are critical for rhabdomyosarcoma cell and tumor growth and survival. For this project, we are indirectly targetting YAP1 and TAZ through inhibition of an upstream kinase that exerts its function by maximizing nuclear YAP1 and TAZ expression. Our preliminary data demonstrates that an inhibitor to that kinase causes a dose-dependent increase in rhabdomyosarcoma cell death and decreases xenograft tumor growth by decreasing active YAP1 and TAZ expression. We are now seeking to combine this kinase inhibitor with conventional chemotherapy salvage agents, thus laying the ground work for an early phase clinical trial. Our preliminary studies show a strong synergistic effect in vitro when combining the kinase inhibitor with vinblastine, an agent commonly used first-line in relapsed or refractory rhabdomyosarcoma cases. During this POST summer project, we will analyze tumors generated from a xenograft study using this combination to confirm target inhibition and to determine tumor kinetics and cancer phenotypes. Ultimately, our hope is that these preclinical studies will lead to an early phase clinical trial studying this novel drug combination in patients with relapsed rhabdomyosarcoma.
