Targeting the Function of Ezrin in Rhabdomyosarcoma
Background
Rhabdomyosarcoma (RMS) is the most common and aggressive soft tissue sarcoma in children and adolescents. RMS is associated with metastasis, which is the major cause of morbidity and mortality in this cancer. Increased expression of ezrin, a membrane-cytoskeleton crosslinking protein, correlates with the degree of metastasis in RMS. Silencing ezrin expression in metastatic RMS cell lines abrogates their invasion potential. The activity of ezrin is regulated by its phosphorylation at Thr567; however, it is not known whether phosphorylated ezrin promotes metastasis in RMS. The activity of ezrin is druggable by a novel, highly specific small molecule (NSC668394) that induces ezrin dephosphorylation. We recently observed that in pre-clinical models of RMS, NSC668394 significantly inhibits cell growth in cell culture and tumor growth in murine xenografts.
Project Goal
In this application, Austin Proudfit will test the hypothesis that NSC668394 will inhibit RMS metastasis by decreasing cell migration. Our specific aims are to investigate if inactivation of ezrin by NSC668394 inhibits (1) RMS migration in vitro, and (2) RMS metastasis in vivo.
Mentored by Neetu Gupta
The Cleveland Clinic Foundation, Cleveland, OH
