Abstract B21: PDE10A overexpression in colon cancer cells and tumors relative to normal colonocytes and colon mucosa

Abstract

Abstract Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme expressed in areas of the brain controlling motor function and cognition. PDE10A has been strongly linked to diseases such as schizophrenia and Huntington's disease, for which PDE10A inhibitors are currently in clinical trials and appear to be well tolerated. Although, PDE10A has limited expression and no known function in peripheral tissues, high levels were measured in colon tumor cells in vitro and in vivo compared with cells derived from normal colon and colonic mucosa (Li et al., Oncogene 2015). PDE10A inhibition by small molecules or genetic silencing attenuated colon tumor cell growth by a mechanism involving cGMP/PKG activation, the suppression of oncogenic β-catenin, and a decrease in TCF transcriptional activity (Li et al., Oncogene 2015). These observations suggest that PDE10A may play an unrecognized role in tumorigenesis and provide a novel therapeutic target for colorectal cancer chemoprevention or therapy. The human colon tumor cell lines, HCT116, HT29, Caco2, and SW480, show elevated expression of PDE10A as compared to the normal colon mucosal epithelial cell line, NCM460, and are more sensitive to PDE10 inhibitors relative to NCM460 cells. Subcutaneous tumors established from HT29 colon tumor cells in athymic mice expressed elevated levels of PDE10A as compared to normal mouse colon tissue. Colon tumors collected from heterozygous APCmin/+FCCC mice displayed an elevation in PDE10A levels as compared to uninvolved mucosa from the APCmin/+FCCC mice and wild type colon mucosa. Overexpression of PDE10A mRNA and protein levels was also observed in colon adenocarcinomas relative to uninvolved colon mucosa in specimens obtained from colorectal cancer patients. These observations, along with recent findings that a novel sulindac derivative (ADT-061) with PDE10A inhibitory activity suppresses tumor formation in the APCmin/+FCCC mouse model of colon cancer without apparent toxicity, suggests that PDE10A provides a novel therapeutic target for cancer cell specific inhibition of tumor growth. Citation Format: Ashley S. Lindsey, Kevin Lee, Joel Andrews, Wen-Chi L. Chang, Veronica Ramirez-Alcantara, Marcus Tan, William Grizzle, Margie L. Clapper, Gary Piazza. PDE10A overexpression in colon cancer cells and tumors relative to normal colonocytes and colon mucosa. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B21.