Development of New Approaches to Target MAP Kinase Pathway in RAS-driven Rhabdomyosarcoma
Current therapies for children with rhabdomyosarcoma are highly toxic and cause lifelong complications for survivors. In addition, high-risk patients have very poor outcomes. More effective and less toxic therapies are needed for these patients. Fusion-negative rhabdomyosarcoma is the more common rhabdomyosarcoma, characterized by frequent cancer-causing mutations in genes called the Ras family genes. We and others have shown that interventions targeting a signaling pathway called the Mitogen Activated Protein Kinase pathway would benefit patients with fusion-negative rhabdomyosarcoma. However, effective strategies to target this pathway are currently lacking. Our proposal will preclinically validate novel approach to target the Mitogen Activated Protein Kinase pathway and define strategies to successfully use this approach for design of less toxic and more effective therapies.
Our proposal focuses on the preclinical development of less toxic and more effective targeted therapies for children with fusion-negative rhabdomyosarcoma, the more common type of rhabdomyosarcoma, characterized by frequent mutations in gene family called the Ras genes. Our preliminary data indicates that a novel inhibitor to target signaling pathway called the Mitogen Activated Protein Kinase pathway could have clinical implications for patients with fusion-negative rhabdomyosarcoma, whose cancer has the Ras mutations. We aim to preclinically validate this inhibitor and define strategies to use it in the clinic in combination with other agents to achieve long-term patient benefit. Accomplishment of our project has the potential to lead to the design of much needed novel therapies for patients with fusion-negative rhabdomyosarcoma.