Abstract 5826: Enhanced anti-tumor effects of selinexor and niraparib in preclinical models of ovarian cancer
Authors: Hua Chang, Trinayan Kashyap, Sophie Debler, Thaddeus J. Unger, Sarah Wang, Keith Mikule, Jing Wang, Mansoor R. Mirza, Sharon Shacham, Yosef Landesman
Journal: Cancer Research (2018)

Abstract Introduction: Selinexor (KPT-330) is a first-in-class oral exportin-1 (XPO1/ CRM1) inhibitor that induces cell cycle arrest and apoptosis in cancer cells through reactivation of tumor suppressor proteins and inhibition of DNA damage repair genes. Here, we studied selinexor in combination with niraparib, an inhibitor of the DNA damage repair proteins PARP1 and 2, in preclinical models of ovarian cancer. Given that both compounds can inhibit DNA damage repair responses, we hypothesized the combination of selinexor and niraparib would enhance cancer cell death by accumulation of DNA damage that cannot be resolved in ovarian cancer. Methods: Selinexor and niraparib alone and in combination were tested in vitro on the BRCA wildtype ovarian cancer cell line A2780. Total RNA and protein were extracted from cell lysates and analyzed by qPCR and immunoblots. In vivo, a subcutaneous A2780 xenograft mouse model was treated with selinexor [10 mg/kg, once per week (M) for three weeks] or niraparib [37.5 mg/kg, once-daily for five days per week (M-F) for three weeks] as single agents or in combination. Tumor growth and body weights were measured for 21 days. Tumors were harvested at the end of the study and analyzed by immunohistochemistry (IHC). Results: Selinexor and niraparib as single agents inhibited A2780 cell proliferation (selinexor IC50: 200nM; niraparib IC50: 800nM). The combination of selinexor and niraparib showed synergistic cytotoxicity in A2780 cells. Increased expression of phospho (S139) H2A.X with the combination confirmed induction of DNA damage. In vivo, the combination enhanced tumor inhibition (51.0% in combination versus 24.3% and 29.6% in selinexor and niraparib respectively) and improved median survival compared to vehicle or each agent alone (18 days in combination group versus 11, 14 and 16 days in vehicle, selinexor, and niraparib groups, respectively). IHC analysis showed enhanced nuclear p53 and p21 staining in selinexor treated tumors as well as in tumors treated with the combination. Increased apoptosis was observed in tumor samples treated with both selinexor and niraparib as compared to vehicle control or each agent alone. Conclusions: Selinexor plus niraparib demonstrated enhanced anti-tumor activity in preclinical models of human ovarian cancer. Since both drugs could inhibit DNA damage repair pathway, the drug combination efficiently accumulated DNA damage, which was associated with reduced cell proliferation, and induced apoptosis. This combination therapy warrants further investigation as a treatment option for patients with ovarian cancer. Citation Format: Hua Chang, Trinayan Kashyap, Sophie Debler, Thaddeus J. Unger, Sarah Wang, Keith Mikule, Jing Wang, Mansoor R. Mirza, Sharon Shacham, Yosef Landesman. Enhanced anti-tumor effects of selinexor and niraparib in preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5826.