Abstract 5777: Ormeloxifene augments the therapeutic response of enzalutamide via targeting androgen receptor splice variant 7

Abstract

Abstract Enzalutamide (ENZ) is a second generation anti-androgen drug in clinical use for the treatment of advanced prostate cancer (PrCa). Use of ENZ has some limitations because of its toxic side effect and developing chemoresistance. It has been shown that expression of androgen receptor splice variant 7 (ARV7) in advanced PrCa is involved in ENZ therapy resistance. It is noteworthy that ENZ does not target AR splice variants because these lack the ligand binding domain of AR. Thus, identification of non-toxic agents which can target ARV7 can improve the enzalutamide therapy response and could be used for the management of advanced stage PrCa. Herein, we identified a clinically approved selective estrogen receptor modulator ormeloxifene (ORM), which augments ENZ therapy response via suppression of ARV7 expression in PrCa cells. We used androgen-independent human prostate cancer cells (22Rv1), which express ARV7 as a model system to study the effect of ORM alone or in combination with ENZ. ORM treatment showed a more potent effect in 22Rv1 cells as compared to ENZ alone. ORM treatment also sensitized the effects of ENZ in 22Rv1 cells. ORM treatment effectively inhibited colony formation ability of 22Rv1 cells; this effect was additive in combination with ENZ. We next performed Western blot analysis of ARV7 in control and ORM treated 22Rv1 cells. ORM effectively inhibited the protein level of AR V7 at 12 hrs post-treatment in 22Rv1 cells; however, no effect was observed with the treatment of ENZ. ORM treatment also inhibited the promoter activity of the AR target gene PSA as determined by luciferase assay. To translate these finding to an in vivo model system, we investigated the chemo-sensitization potential of ORM in a 22Rv1 cell-derived xenograft mouse model. ORM treatment (200 µg/mouse three times a week for 8 consecutive weeks) significantly (P<0.01) inhibited prostate tumor growth. However, we did not observe any significant tumor growth inhibition with oral administration of ENZ (10 mg/kg body weight). ORM treatment improved the therapeutic response of ENZ in 22Rv1 cells derived xenograft mouse model as monitored by significant (P<0.01) decreases in both tumor volume and tumor weight as compared to ENZ treatment alone. Our findings indicate that ORM alone or in combination with ENZ could be an effective therapeutic approach for the treatment of advanced PrCa. Citation Format: Bilal B. Hafeez, Andrew E. Massey, Vivek K. Kashyap, Mohammed Sikander, Advit Shetty, Mehdi Chaib, Hassan Mandil, Shabnam Malik, Mohan M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Ormeloxifene augments the therapeutic response of enzalutamide via targeting androgen receptor splice variant 7 [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 5777.