Abstract 3501: Entinostat enhances the efficacy of olaparib in preclinical models of ovarian cancer

Abstract

Abstract Introduction: Ovarian cancer is a rare but often fatal disease and a leading cause of gynecologic cancer death, in the United States. Poly ADP ribose polymerase inhibitors (PARPi) are promising new drugs that are most effective in patients with tumors with altered homologous recombination (HR) DNA repair genes, particularly BRCA1/2. To expand their clinical utility, PARPi are being tested in combination with other drugs. Our group has published that histone deacetylase inhibitors (HDACi) sensitize HR proficient BRCA wild-type ovarian cancer cells to PARPi. We have developed an investigator-initiated phase 1/2 clinical trial of the PARPi olaparib combined with the HDACi entinostat in patients with recurrent, HR proficient/BRCA wild-type ovarian cancer. Objective: To test the effects of a novel combination of olaparib and entinostat in preclinical models of BRCA wild-type ovarian cancer. Methods: HR proficient BRCA wild-type SKOV3 and ID8 ovarian cells were treated with Entinostat followed by Olaparib alone or the combination of Entinostat and Olaparib. Treated and control cells were analyzed for cell proliferation by sulforhodamine B assays, clonogenicity, and DNA damage by Comet assays. SKOV-3-luciferase cells were injected intraperitoneally into NOD-SCID mice. Mice were randomized into 4 treatment groups and treated with vehicle, entinostat, olaparib, or the combination. The mice were monitored for toxicity and by bioluminescence imaging (BLI). At sacrifice, tumor burden was quantified. Results: In cell culture assays, entinostat significantly enhanced the sensitivity of SKOV3 and ID8 cells to Olaparib. Entinostat combined with olaparib led to synergistic reductions in cell proliferation and clonogenicity in SKOV-3 and ID8 ovarian cancer cells, compared to each drug alone. Evidence of DNA damage was enhanced by the drug combination. In the SKOV3-luc xenograft mouse model, a significant reduction in tumor burden in the group of mice treated with the combination of entinostat and olaparib, compared to each drug alone. There was no significant toxicity with drug treatment. Conclusion: Entinostat sensitizes ovarian cancer cells to Olaparib in vitro and in vivo. Experiments in ID-luciferase and patient-derived xenograft models are ongoing. These preclinical models are powerful tools that will be used to discover markers and mechanisms of sensitivity and resistance to inform the parallel clinical trial. Citation Format: Vijayalaxmi G. Gupta, Yoskaly Lazo Fernandez, Katherine Roby, Harsh Pathak, Jeff Hirst, Andrew J. Wilson, Andrew Godwin, Dineo Khabele. Entinostat enhances the efficacy of olaparib in preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3501.