Abstract LB-254: High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism

Abstract

Abstract Background: Inhibitors of apoptosis (IAPs) are attractive anti-cancer therapeutic targets as a mechanism to sensitize cancer cells to apoptosis. IAPs are overexpressed in ovarian cancer and portend a poor prognosis. SMAC- mimetics are IAP antagonists that have shown in vitro and in vivo antitumor activity in ovarian cancer, but preclinical and clinical studies suggest SMAC mimetics may be more effective in combination therapies. Methods: Birinapant (B) was initially screened in combination with each of 1,912 compounds using an automated acoustic drug dispensation system in 6×6 matrices. Seventy compounds were chosen from the initial screen, based on synergistic characteristics, and verified in 10×10 matrices. The most clinically rational drug combinations with B were further evaluated in 8 high-grade serous ovarian cancer cell lines (CAOV3, CAOV4, OV-90, OVCAR4, OVCAR5, OVCAR8, PEO1, PEO4), focusing on 3 synergistic (docetaxel, panobinostat, volasertib) and 2 antagonistic combinations (cisplatin, olaparib) for exploration of mechanism. Combination index was determined using Compusyn software. Results: Specific classes of drugs were identified to have synergism with B, including taxanes, HDAC inhibitors, and PLK1 inhibitors, while platinum agents and PARP inhibitors were found to be antagonistic. Four of the 8 cell lines were sensitive to B. Caspase-Glo 3/7 assay was performed in B-sensitive cell lines and confirmed increased caspase-3 activity in the combination treatments. Ongoing studies include genomic analysis, mechanistic interrogation, and in vivo xenograft studies. Conclusions: B is a promising novel therapy for use in combination treatment for ovarian, fallopian tube, or primary peritoneal cancers. Our findings provide insight on optimal therapies to combine with B, and constitute a foundation for further evaluation of predictive and pharmacodynamic biomarkers to select the patient population most likely to respond to this targeted therapeutic approach. Citation Format: Kristen Bunch, Ian Goldlust, Craig Thomas, Lidia Hernandez, Rajarshi Guha, Christina Annunziata. High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-254. doi:10.1158/1538-7445.AM2015-LB-254