Abstract A30: Novel non-COX inhibitory sulindac derivative with PDE10 inhibitory activity reduces incidence and multiplicity of colorectal adenomas in the APC+/min-FCCC mouse model

Abstract

Abstract Sulindac has been reported to reduce the number and size of precancerous colonic adenomas in patients with familial adenomatous polyposis (FAP), but is not recommended for long-term use as a cancer chemopreventive drug because of potentially fatal toxicities associated with cyclooxygenase (COX) inhibition. We report here a novel sulindac derivative, ADT-061, that lacks COX-1 and COX-2 inhibitory activity, yet potently and selectively inhibits colon tumor cells with IC50 values of 0.3-0.5 μM with no significant effect on the growth of normal colonocytes. By comparison, sulindac sulfide inhibits colon tumor cell growth with IC50 values of 40-60 μM, and has only modest tumor cell selectivity. ADT-061 inhibits phosphodiesterase 10A (PDE10), which increases intracellular cGMP levels, thus activates protein kinase G, suppresses nuclear levels of β-catenin, and induces cell cycle arrest and apoptosis, all within the same concentration range that inhibits tumor cell growth. ADT-061was evaluated for chemopreventive activity in the APC+/min-FCCC mouse model of colon cancer, which harbors colorectal adenomas that express PDE10. Colonoscopy exams were initially performed on all mice to ensure the absence of colorectal adenomas prior to treatment. At 7-8 weeks of age, male mice were treated with ADT-061 (1000ppm and 1500ppm) in the diet for 14 weeks. ADT-061 reduced the incidence of colorectal adenomas from 95.8% in the control group to 73.9% in the 1000ppm group (p=0.048), and 59.1% (p=0.004) in the 1500ppm group. Control untreated mice had an average of 2.98 colorectal adenomas per mouse, while mice treated with 1000ppm and 1500ppm ADT-061 had an average of 2.04 (p=0.102) and 1.91 (p=0.039) adenomas per mouse, respectively. These observations suggest that ADT-061, or analogs thereof, merit further drug development efforts for colorectal cancer chemoprevention. Citation Format: Kevin J. Lee, Xi Chen, Jacob Valiyaveettil, Ashley S. Lindsey, Joel Andrews, Veronica Ramirez-Alcantara, Adam B. Keeton, Gary A. Piazza, Margie L. Clapper, Wen-Chi L. Chang. Novel non-COX inhibitory sulindac derivative with PDE10 inhibitory activity reduces incidence and multiplicity of colorectal adenomas in the APC+/min-FCCC mouse model. [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 A30.