Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer

Abstract

The next-generation antiandrogen MDV3100 prolongs overall survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patient responses are variable, and survival benefit remains relatively small. Developing effective modality to improve MDV3100 efficacy is urgently needed. Recent evidence suggests that constitutively active androgen receptor splice variants (AR-Vs) drive resistance to MDV3100. In our study, we show that methylselenol prodrug downregulates the expression and activity of both the full-length AR (AR-FL) and AR-Vs. The downregulation is independent of androgen and could be attributable to repressed transcription of the AR gene. Cotreatment with methylselenol prodrug and MDV3100 suppresses AR signaling more dramatically than either agent alone, and synergistically inhibits the growth of CRPC cells in vitro. The combinatorial efficacy is observed in not only AR-V-expressing cells but also cells expressing predominantly AR-FL, likely owing to the ability of the two drugs to block the AR signaling cascade at distinct steps. Ectopic expression of AR-FL or AR-V7 attenuates the combinatorial efficacy, indicating that downregulating AR-FL and AR-V7 is importantly involved in mediating the combinatorial efficacy. Significantly, methylselenol prodrug also downregulates AR-FL and AR-Vs in vivo and substantially improves the antitumor efficacy of MDV3100. These findings support a potential combination therapy for improving MDV3100 efficacy, and provide a rationale for evaluating the clinical application of combining methylselenol prodrug with MDV3100 for the treatment of CRPC. What's new? The next-generation anti-androgen MDV3100 prolongs overall survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patient responses are variable and survival benefit remains small, making the improvement of MDV3100 efficacy urgently needed. This study provides the first example of a rationally-designed, potentially effective combination modality for improving MDV3100 efficacy against CRPC. Methylselenol prodrug potentiates MDV3100 efficacy, an effect that is associated with the ability of methylselenol prodrug to downregulate androgen receptor and its constitutively-active splice variants. The findings provide a rationale for evaluating the clinical application of combining methylselenol prodrug with MDV3100 for the treatment of castration-resistant prostate cancer. © 2013 UICC.