AAV9 Gene Therapy Using a Novel Engineered MIS to Treat Ovarian Cancer

There is a compelling unmet need for any ovarian cancer therapy effective against chemoresistant recurrences, and gene therapy approaches in cancer have been largely underutilized. Furthermore, gene therapy allows delivery of Mullerian Inhibiting Substance (MIS) at concentrations hitherto unachievable in in vivo models. Thus, AAV9-delivered MIS permits testing in vivo, for the first time, the hypothesis that a fetal inhibitor can be developed as an effective anti-cancer agent, initially against patient-derived xenografts (PDXs) in immunosuppressed mice. We hypothesized that MIS will be an effective and safe therapy for women with recurrent ovarian cancer, which is usually refractory to chemotherapy and most often a death sentence. Our preliminary results indicate that MIS is a potent inhibitor of ovarian cancer in vitro and in vivo; however, only a subset of tumors respond to MIS therapy, and both the mechanism of inhibition and the determinants of response remain poorly understood. The purpose of the project is to test the response to MIS using patient-derived primary ovarian cancer cells, elucidate the mechanism of action using next generation sequencing technologies, identify biomarkers of response, and test the efficacy of MIS gene therapy approach in clinically relevant ovarian cancer models.