Abstract 4652: Repurposing mebendazole in combination with PRIMA1MET for ovarian cancer therapy

Abstract

Abstract Background High-grade serous ovarian carcinoma (HGSOC) is the most aggressive subtype of ovarian cancer. Standard treatment options have a poor survival rate given high risk of recurrence with chemoresistant disease. Hence, there is a need for novel therapy to treat HGSOC. The repurposed drug mebendazole (MBZ) is effective against cancer cells at lower doses. The effectiveness of anti-cancer drugs in treating HGSOC is significantly reduced due to p53 mutations, which are found in most HGSOC (96%) tumors. Chemoresistance may be overcome by combination with p53 reactivator drugs such as PRIMA-1MET. The synergistic drug combination would significantly increase the efficacy of these drugs as well as decrease the overall toxicity by lowering effective doses of drugs. We hypothesize that combination of MBZ and PRIMA-1MET may be a synergistic and effective treatment for HGSOC. Methods The combination index (CI) of MBZ and PRIMA-1MET was determined in HGSOC cells with different endogenous p53 mutants (MES-OV R282W, ES2 S241F), exogenously expressed p53 mutants (SKOV3 R273H, SKOV3 R248W), p53 null (SKOV3) and wild type p53 (A2780 WT) cells. The mechanism of drug combination was determined by immunoblotting of intrinsic and extrinsic apoptosis pathways, measurement of soluble/assembled tubulins and reactive oxygen species (ROS) generation analysis. In vivo validation of drug combination is currently being performed using an intraperitoneal tumor model of MES-OV GFP/Luc cells in athymic nude mice. Results p53 missense mutant cells (IC50- 1.5 µM) were significantly more sensitive to MBZ compared to p53 null cells (IC50-7.8µM). The combination index of MBZ and PRIMA-1MET indicated synergism (CI= 0.3 to 0.7) in all HGSOC cells except SKOV3 R248W p53, which was nearly additive (CI= 0.90 to 1.10). The average dose reduction index (DRI) of this drug combination is 8.5 fold less than the single dose. The protein level of p53 was increased in both PRIMA-1MET and combination treated groups, and the p21 level was increased in MBZ and combined treated groups. The increased level of cleaved caspase 9 & 3 and cleaved PARP level confirmed that this drug combination is effective in inducing apoptosis in HGSOC cells. Moreover, the decreased level of tubulin polymerization in the MBZ and combination treated groups proves that MBZ affected the microtubule assembly known to lead to mitotic arrest and cell death. Conclusion The combination of MBZ and PRIMA-1MET had a synergistic effect and induced apoptosis by modulating microtubule assembly and p53 level in HGSOC cells with different p53 mutations. The drug combination may have a potential benefit to HGSOC patients that recur due to chemoresistance. The significant dose reduction index will allow lower doses of drugs to be used thus reducing the overall toxicity of these drugs. Acknowledgment Funded by PHF clinician scientist development grant. Citation Format: Sugantha Priya Elayapillai, Satish Kumar Ramraj, Doris M. Benbrook, Camille C. Gunderson. Repurposing mebendazole in combination with PRIMA1MET for ovarian cancer therapy [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 4652.