Abstract POSTER-BIOL-1336: Investigating the role of phosphodiesterase 10A as a novel target in ovarian cancer

Abstract

Abstract Cyclic nucleotide phosphodiesterases (PDEs) play major roles regulating cell signaling by hydrolyzing the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 10A (PDE10A) is one of 21 PDEs encoded in the human genome. Its predominant expression in the brain striatum has guided intensive investigations on the therapeutic potential of PDE10A in psychiatric and neurological disorders, leading to several PDE10A inhibitors in clinical trials for schizophrenia and Hungtington's disease. Recently, we described for the first time an oncogenic role for PDE10A in colorectal cancer (N. Li et al. 2014 Oncogene 1-11). Our published data showed that PDE10A is overexpressed in colon tumor cells when compared to normal colonocytes, and that pharmacological inhibition or genetic knockdown of PDE10A suppresses colon tumor growth. Here, we are investigating the role of PDE10A in ovarian cancer and its potential as a novel therapeutic target. We detected expression of PDE10A in several ovarian cancer cell lines (SKOV3, SKOV3ip1, A2780, A2780-CP70, OV-90, ES-2 and TOV112D) by western-blotting and quantitative RT-PCR. In addition, our preliminary analysis revealed PDE10A expression in tumors and matched normal tissues from eight patients of ovarian cancer. Finally, we developed novel small molecule compounds targeting PDE10A which potently inhibit growth of all these ovarian cancer cell lines at low micromolar or sub-micromolar concentrations. Future work will focus on i) expanding the cohort of ovarian cancer patient tissues to analyze expression levels of PDE10A by western-blotting, quantitative RT-PCR and immunohistochemistry; ii) genetic silencing of PDE10A by siRNA/shRNA to investigate its role regulating cell proliferation, apoptosis, and cGMP/cAMP cell signaling in ovarian cancer; iii) investigate the signaling pathways suppressed by our novel PDE10A inhibitors. Our studies will determine the potential of using PDE10A as a novel therapeutic target for the treatment and chemoprevention of ovarian cancer. Citation Format: Luciana Madeira da Silva, Kevin Lee, Gary A. Piazza, Lavanya Bachaboina, Rodney P. Rocconi, Jennifer Scalici. Investigating the role of phosphodiesterase 10A as a novel target in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1336.