Abstract 3212: ONC201 shows efficacy in BRCA-deficient cancer cells and synergy with PARP inhibitors in glioblastoma, breast, prostate, and ovarian cancers

Abstract

Abstract BRCA1 and BRCA2 are involved in control of DNA repair by homologous recombination (HR). Germline mutations in these genes substantially increase lifetime risk of developing breast, ovarian and other cancers. BRCA-deficient tumors show increased sensitivity to therapies that target defective HR. Sporadic tumors lacking germline BRCA mutations but sharing the molecular features of BRCA-mutant tumors may respond to these types of therapies as well. PARP inhibitors represent a form of targeted therapy for HR-deficient tumors that have been approved in ovarian cancer and are being tested in clinical trials in breast cancer, metastatic castration-resistant prostate cancer, and glioblastoma. Our lab has previously identified a small molecule called ONC201 in a screen for compounds capable of inducing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Our lab has previously reported that ONC201 induces an integrated stress response that involves ATF4/CHOP and inactivates pro-survival kinases Akt and ERK. The latter leads to decreased phosphorylation of transcription factor FOXO3a, its nuclear translocation, and induction of transcription of the target gene TRAIL. A first-in-human clinical trial showed that the compound is well tolerated, achieves a therapeutic pharmacokinetic profile, exhibits biological activity. It has since entered multiple phase I/II trials. ONC201 has anti-proliferative and pro-apoptotic effects in a wide range of tumor types including BRCA-deficient breast and ovarian cancers (n=10), with GI50 values in the low micromolar range. Treatment with ONC201 induces surface TRAIL and inhibits Akt activity in BRCA deficient breast and ovarian cancers. PARP inhibitors have been previously shown to upregulate DR5 through transcription factor CHOP, sensitizing solid tumors to TRAIL. Resistance to PARP inhibitors can occur through PI3K/Akt pathway activation, and PI3K/MEK blockade improves their anti-tumor effects. We observed synergy between ONC201 and PARP inhibitors olaparib and rucaparib in BRCA-deficient breast and ovarian cancer cell lines in cell viability assays with combination indices (CI) ranging from 0.4 - 0.8. Robust synergy was also observed in prostate cancer and glioblastoma cells. The mechanisms of the observed synergy are currently under investigation. These results indicate that ONC201 possesses single agent activity in BRCA-deficient cancer cells and that the combination of ONC201 with PARP inhibitors represents a promising synergistic therapeutic approach that could be exploited in multiple solid tumors. Citation Format: Marie D. Baumeister, Ozan C. Küçükkase, Varun V. Prabhu, David T. Dicker, Josh E. Allen, Wafik S. El-Deiry. ONC201 shows efficacy in BRCA-deficient cancer cells and synergy with PARP inhibitors in glioblastoma, breast, prostate, and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3212. doi:10.1158/1538-7445.AM2017-3212