Abstract 2126: Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of androgen independent prostate cancer progression.

Introduction: Prostate cancer (PCa) is the second most common cause of death from cancer and the leading cancer diagnosed in the US men. Approximately 1 in 6 American men will be diagnosed with prostate cancer during his lifetime. Estimated new cases and deaths from prostate cancer in the United States for 2012 include: 241,740 new cases and 28,710 deaths. Initial treatment for metastatic PCa involves androgen ablation therapy, which causes regression of androgen-dependent tumors. However they all eventually relapse resulting in recurrent androgen independent prostate cancer (AIPC). Methods: This study aims at assessing the role of Hedgehog (Hh) and Androgen receptor (AR) signaling in the development of AIPC. Quantitative RT-PCR analysis was performed for AIPC cells in vitro and for AIPC xenograft after castration, to assess the levels of Hh and AR signaling components. Hh inhibitors, LDE225 (Novartis) and Cyclopamine, and Androgen receptor inhibitor Pyrvinium pamoate were tested individually and in combination to assess the suppression of AIPC progression both in vitro and in vivo. AR-responsive and Gli-responsive promoter-luciferase assay and MTT assay were used for in vitro studies. Intraperitoneal administration of drugs and bioluminescence imaging for monitoring orthotopic tumors in mice were used to study the effect of drugs on the growth of AIPC in vivo. Results: We demonstrate that androgen deprivation leads to increase in Hedgehog (Hh) signaling components in the AIPC cells in vitro and in vivo. AIPC cells also show increased sensitivity to low concentrations of androgen, suggesting increased androgen receptor expression. Together, these results suggest that increased Hh signaling and androgen receptor expression in the absence of androgen agonist plays an important role in the development and progression of AIPC. Our results show that inhibiting either Hh or androgen receptor signaling pathway individually was not effective in preventing AIPC cell proliferation in vitro as well as in inhibiting xenograft tumor growth in mice. In contrast, combination of an Hh pathway inhibitor with an androgen receptor inhibitor synergistically suppressed the growth of AIPC cells in vitro as assessed by MTT assay and reduced tumor burden in a mouse xenograft model of AIPC as compared to individual treatments.Conclusion: Upregulated Hh signaling and AR expression mediates development and progression of AIPC. Combined inhibition of Hh and androgen receptor signaling pathways may be a novel effective therapeutic strategy for the treatment of androgen independent prostate cancer. Citation Format: pramod gowda, Jianhong Deng, Sweta Mishra, LuZhe Sun. Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of androgen independent prostate cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2126. doi:10.1158/1538-7445.AM2013-2126