Abstract 4810: Targeting androgen receptor in combination with cisplatin: Effective treatment strategy for muscle invasive bladder cancer

Abstract

Abstract Background: Bladder cancer is one of the major causes of cancer death in US and worldwide. Cisplatin is a key component of chemotherapeutic regimens employed in the treatment of advanced bladder cancer. The role of androgen and androgen receptor (AR) signaling in bladder cancer remains uncharacterized. Aim: The aim of the study is to delineate the role of AR in bladder cancer and to determine whether combination of AR inhibitor, enzalutamide (Enz) and cisplatin-based therapies effectively inhibit the growth of muscle invasive bladder cancer (MIBC). Methods: AR expression was determined in 75 human bladder cancer specimens and in a panel of bladder cancer cell lines. Cells grown in charcoal stripped media supplemented with dihydrotestosterone (DHT) were treated with cisplatin, enzalutamide (AR inhibitor), or a combination of both. Cellular/phenotypic analysis including MTT assay, apoptotic assay, migration as well as invasion assays and molecular analysis including western blotting, real time PCR analysis were performed. Isobologram analysis for the combination was performed and analyzed with CompuSyn. Experiments were repeated in triplicates and analyzed with unpaired Student's t-test and one way ANOVA *p≤0.05, **p≤0.01, ***p≤0.001. Results: AR expression was seen in around 40% of bladder cancer patients. Inhibition of AR signaling by enzalutamide effectively inhibited the growth of AR+ MIBC cells. Interestingly, enzalutamide in combination with cisplatin (Enz + Cis) synergistically inhibited the proliferation of MIBC cells, TCCSUP (CI: 0.42, 1.25 + 5 μM) and J82 (CI: 0.79, 2.5 + 5 μM) at low concentrations of enzalutamide and cisplatin resp.. The molecular studies revealed the induction of DNA damage markers (pATM, pATR, pChk1, pHis) and enhanced expression of the pro-apoptotic genes (Bax, caspases-3 and PARP) in Enz+Cis treated AR+ MIBC cells. In addition, we demonstrated abrogation of invasive and migratory potential with Enz+Cis treatment, by downregulation of the mesenchymal markers (N-cadherin, slug, β-catenin, and vimentin) in both cell lines. Our studies suggest combination of Enz + Cis may be effective in patients with AR+ MIBC. Conclusion: Combination of cisplatin and AR inhibition effectively inhibit bladder tumor growth and migration, and hold promise as synergetic therapies for AR+ bladder cancer patients. Citation Format: Ashish Tyagi, Balaji Chandersekaran, Samarpit Rai, Houda Alatassi, Ahmed Q. Haddad, Murali K. Ankem, Chendil Damodaran. Targeting androgen receptor in combination with cisplatin: Effective treatment strategy for muscle invasive bladder cancer [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 4810.