Abstract 5798: Elucidating novel role of bezafibrate, a PPARα agonist as potential anticancer agent in the treatment of renal cell carcinoma

Abstract

Abstract Renal Cell Carcinoma (RCC) accounts for 2 - 3% of all the malignant diseases worldwide, leading to a mortality of around 1.7 lakh every year. Incidence of RCC in eight major markets has been predicted to increase by 63% over the period from 2013 to 2023. The current treatment modules are dominated by anti-angiogenic agents and tyrosine kinase inhibitors (TKIs). In the coming years, Programmed Cell Death - 1 inhibitors are set to replace TKIs as the preferred standard of care (SOC) drug. However, owing to the long waiting periods associated with these agents to reach the market, there is a significant unmet medical need for development of new drugs. Discovery and development of new drugs is an expensive process associated with long incubation periods. Hence repurposing of an already existing drug is an attractive and cost effective substitute. We have identified Bezafibrate, a FDA approved drug for the treatment of hyperlipidaemia, as a potential anti-cancer agent against RCC. It acts as a PPARα agonist, thereby promoting the uptake and catabolism of fatty acids. Several studies have shown its role in inhibition of cyclin-dependent kinases, thereby arresting the cells in G0/G1 phase of cell cycle. It has been reported to be successfully used in combination with other respective SOC drugs in the treatment of leukaemia and colorectal cancer. However, the efficacy of bezafibrate as a single agent or in combination with SOC for the treatment of renal cancer has not yet been reported. In this study, we have evaluated Bezafibrate against a panel of 10 RCC cell lines including patient derived cells (PDX). It displayed an in vitro dose dependent cytotoxicity with a mean IC50 of 1222 μM and 985 μM in a 2D and 3D setup respectively. Importantly, the combination of sunitinib, a SOC and bezafibrate showed an overall additive effect in suppressing colony formation by 1183L (PDX) and SN12C cell lines seeded on soft agar coated plates. Further, in vivo efficacy studies were performed in sub cutaneously implanted A498 cells in athymic nude mice xenograft model treated with drug alone and in combination. Sunitinib and bezafibrate alone exhibited a mean tumor growth inhibition of 50.78% and 31.59% respectively on day 20 as compared to the control group. Interestingly, the combination was able to inhibit the growth of tumor by 66.76% on the same day (n = 7). Moreover, the cell cycle analysis, differential gene and protein expression studies involving markers for cell cycle regulation, proliferation and apoptosis show promising results. Thus, our results indicate bezafibrate as a promising candidate against RCC. Furthermore, the novel combination involving Bezafibrate and Sunitinib synergistically ameliorates the proliferation and migration potential of the cancer cells. Hence, this combination may be significantly helpful in reducing the dosage of Sunitinib without compromising on its therapeutic potential. Citation Format: Srikanth Iyer, Jeevan Ghosalkar, Geena Malhotra, Kalpana Joshi. Elucidating novel role of bezafibrate, a PPARα agonist as potential anticancer agent in the treatment of renal cell carcinoma [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 5798.