Abstract A12: Combined EZH2 and PI3K inhibition as a novel therapy for treatment of castration resistant prostate cancer

Abstract

Abstract Prostate cancer is the most frequently diagnosed non-dermatological malignancy in North American men. Presently, preventative testing and castration therapies are the only measures that effectively decrease mortality. However, these therapies are not effective in the case of the advanced disease, for which there is still no cure. As such, there is an unmet medical need to develop more effective therapies for castration-resistant, metastatic tumors. Surprisingly, there are but a few things known about the signals that drive and maintain advanced disease. The PI3K/AKT signaling pathway is frequently deregulated in human malignancies and is activated in a majority of advanced stage carcinomas of the prostate. More recently, a member of PRC2 complex, EZH2, has been reported to be a marker and driver of late stage disease. Based on this knowledge about the key disregulated signaling pathways in prostate cancer, we decided to explore them as potential therapeutic avenues. We found that both genetic and biochemical inhibition of EZH2 results in reduced proliferation and transformation in soft agar. Similarly, treating cells with a PI3K specific inhibitor, GDC- 0941 produces only a cytostatic effect, an observation that is supported by a body of literature suggesting that GDC-0941 is ineffective as a mono-therapy drug. To this end we decided to explore the combination of both EZH2 and PI3K inhibitors and have found that simultaneous suppression of these two important oncogenic signals, kills androgen-dependent (AD) and independent (AI) prostate cancer cells in vitro and in vivo. Knock-down of another member of PRC2 complex, SUZ12, phenocopies this cytotoxicity when combined with PI3K inhibitor, suggesting that EZH2 role is PRC2-dependent. These preliminary data suggest specific cooperation of EZH2 and PI3K/AKT signaling pathways in assuring cell survival and maintenance of tumorigenicity in prostate cancer cells. Currently we are exploring the potential downstream effectors that could be responsible for the synergy that we observe upon combination treatment. Citation Format: Miriam Enos. Combined EZH2 and PI3K inhibition as a novel therapy for treatment of castration resistant prostate cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A12.