Abstract 4817: EP-100 sensitizes BRCA wild-type ovarian cancer cells to PARP inhibitor

Abstract

Abstract EP-100 is a synthetic lytic peptide specific for targeting LHRH receptors on cancer cells that is being clinically tested for treatment of ovarian cancer. In this study, we aimed to identify combination approaches with EP-100 in ovarian cancer models. We carried out a series of in vitro (MTT assay, immunoblot analysis, Q-PCR, reverse phase protein array (RPPA), comet assay and immunofluorescence staining) and in vivo (orthotopic mouse model) experiments in ovarian cancer models to determine the biological effects of EP-100 alone and in combination with standard of care drugs. We first examined the cytotoxic effects of EP-100 alone on 8 ovarian cancer cell lines with variable expression level of LHRH receptors and the IC50 values ranged from 0.5 to 2.0 µM. We then tested the effect of combining EP-100 with standard drugs (e.g., cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib) on ovarian cancer cells. Of those drugs, we found that combination of EP-100 and olaparib was highly synergistic in drug sensitive and multi-drug resistant ovarian cancer cell lines (HeyA8, HeyA8-MDR, A2780, and A2780CP20). The combination indices (CI) were < 0.9 at the ED50 level. Furthermore, the nuclear foci of γH2AX were significantly increased in combination group of EP100 and olaparib after 24 h incubation compared with control, EP-100 alone, or olaparib alone groups (p < 0.0001, ANOVA). In addition, there was increased DNA accumulation in tails using comet assay after treating cells with EP-100 and olaparib for 24 h (p < 0.001, ANOVA). RPPA results identified that PI3K/AKT pathway can be blocked significantly by the combination treatment. The study in HeyA8 xenograft mouse models showed that mice treated with EP-100 and olaparib had the lowest tumor weight (0.06 ± 0.05 g) compared with those treated with vehicle (1.19 ± 0.39 g, p < 0.008), EP-100 alone (0.62 ± 0.28 g, p < 0.008), and olaparib alone (0.50 ± 0.22 g, p < 0.01). EP-100 has efficacy in preclinical models of ovarian cancer, especially in combination with olaparib. Our findings suggested that combining EP-100 with olaparib could be a promising therapeutic strategy for ovarian cancer. Citation Format: Shaolin Ma, Sunila Pradeep, Sherry Wu, Mark Seungwook Kim, Wei Hu, Selanere Mangala, Robert L. Coleman, Anil K. Sood. EP-100 sensitizes BRCA wild-type ovarian cancer cells to PARP inhibitor [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 4817.