Abstract 5394: Dual inhibition of the androgen receptor by ligand blockade and antisense-mediated downregulation is associated with synergistic antitumor activity model of prostate cancer

Abstract

Abstract Background: Although new agents to treat prostate cancer have recently been approved, and new investigational drugs (Abiraterone and MDV3100) that mediate hormone deprivation show promising data from late-stage clinical trials, these therapies typically extend overall survival up to 4 months in patients with advanced disease who have failed conventional androgen deprivation therapy. Hence, there continues to be great medical need. EZN-4176 is a novel LNA-based antisense oligonucleotide (EZN-4176) that down regulates androgen receptor (AR) expression. Previously, antitumor activity of EZN-4176 in multiple xenograft models including both androgen-sensitive and castrate-resistant tumors was shown. More importantly, a synergistic effect was also found when EZN-4176 was combined with MDV3100. Further exploration of the mechanistic underpinning of the effect was explored here. Methods: The mRNA, growth, luciferase activity, protein, and prostate specific antigen (PSA) were evaluated by qRT-PCR, MTT, SteadyGlo, western blot analysis, and ELISA assay, respectively. The effect of EZN-4176 on AR transcriptional activity was evaluated in cells stably express luciferase gene regulated by AR. In vivo, the effect of EZN-4176 on AR transcriptional activity was evaluated in a bone tumor model developed by intratibia injection of C4-2b-AR-luc cells. Results: Combination of EZN-4176 with MDV3100 resulted in a much improved inhibitory effect in colony formation assay in vitro. This effect was not associated with enhanced efficiency of AR mRNA down-modulation as treatment with EZN-4176 with or without MDV3100 showed similar effects on the level of AR mRNA. However, when AR transcriptional activity was examined, we found that the combined effect was greater than each agent alone. In C4-2b-AR-luc bone tumor model, EZN-4176 potently and specifically down-modulated AR-luciferase reporter activity. Further examinations of the anti-tumor effect in this model will help understand the potential of the combinatorial effect in a highly relevant disease model. Conclusions: Our preliminary data suggest that the synergistic anti-tumor effect of EZN-4176 in combination with MDV3100 is in part associated with much reduced transcriptional activity of AR. EZN-4176 alone or in combination with anti-androgens offers great potential in treating patients with advanced prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2011-5394