Abstract B41: Targeting androgen-independent prostate cancer through epigenetic reprogramming

Background and aim of the study: The mainstay of therapy for patients with metastatic prostate cancer, including castration resistant disease (CRPC), is hormonal therapy targeting the androgen receptor (AR). However, tumors ultimately develop treatment resistance, which can include epithelial plasticity associated with loss of AR expression, clinical aggressiveness, and pathologic features of small cell or neuroendocrine carcinoma (NEPC). We recently preformed integrative molecular analyses of metastatic tumors from a large cohort of CRPC and NEPC patients. Emerging data from this study points to a key role of the Polycomb gene EZH2 and the epigenome in driving this adaptive response mechanism. In this study we are now exploring the hypothesis that the epigenetic modifier, EZH2, can lead the adaptive response towards an androgen-independent phenotype and towards the appearance of neuroendocrine features. Results: Based on the driving role of EZH2 in other tumor types and significant overexpression in NEPC tumors (confirmed at a protein level on Tissue Microarray), we evaluated the effects of the EZH2 inhibitor, GSK343, in NEPC cells (NCI-H660) and prostate adenocarcinoma cells (LNCaP and DU145) in 3D Matrigel cultures. GSK343 effectively inhibited H3K27me3 and resulted in a significant reduction of NCI-H660 viability, measured with an ATP-based assay, whereas LNCaP and DU145 cells were minimally affected after 7 or 14 days of treatment. Using a nanosting assay we also demonstrated a significant increase in the expression of AR signaling genes (such as PSA, PSMA) and decrease in NEPC-associated genes (chromogranin A, AURKA, ENO2) when neuroendocrine cells are treated with EZH2 inhibitor. These data suggest a modulation of the neuroendocrine phenotype via EZH2. We therefore extended these drug studies including patient-derived organoid models including both CRPC and NEPC organoids, and we observed similar results with preferential sensitivity of the AR-negative NEPC organoids to the AR-positive CRPC organoid, with similar reversion of downstream AR/NEPC gene expression. Conclusions: There is no approved drug that can specifically target AR- independent NEPC tumors. The restricted set of therapeutic options against this subtype of prostate cancer and consequent dismal outcome stem in part from our incomplete understanding of the molecular events underlying its pathogenesis. The discovery that epigenetics can be a key process in distinguishing tumors that are AR-independent and at high risk for NEPC progression represents an important step to highlight the use of epigenetic modifiers as therapeutic agents for this subtype of prostate cancer. Citation Format: Loredana Puca, Dong Gao, Myriam Kossai, Joanna Cyrta, Clarisse Marotz, Juan Miguel Mosquera, Theresa Y. MacDonald, Andrea Sboner, Rema Rao, Yu Chen, Mark A. Rubin, Himisha Beltran. Targeting androgen-independent prostate cancer through epigenetic reprogramming. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B41.