Abstract 1937: Inhibition of a novel cancer target, PDE10, suppresses Wnt/β-catenin signaling and colon tumorigenesis: Benefits from combining with ornithine decarboxylase inhibitors

Abstract

Abstract Sulindac has been shown in clinical trials to reduce the number and size of precancerous colon adenomas, but is not recommended for the long-term management of polyposis syndromes because of potentially fatal toxicities resulting from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis. Here we characterize the activity of a non-COX inhibitory sulindac derivative, MCI-030, that inhibits a novel cancer target, phosphodiesterase 10A (PDE10), recently reported to be overexpressed in colon tumors and essential for tumor cell growth (Oncogene 34:1499-509, 2015). PDE10 is an attractive cancer target because of limited expression and no known function in normal peripheral tissues. MCI-030 potently and selectively inhibits the growth of multiple colon tumor cell lines expressing PDE10 with IC50 values of 0.3 μM, but does not affect the growth of normal colonocytes (NCM460) that do not express PDE10. Sulindac inhibits colon tumor cell growth with IC50 values approximately 200 fold higher and modest tumor cell selectivity. MCI-030 is PDE10 selective, but sulindac inhibits multiple PDE isozymes (PDE2, 3, 5, and 10). MCI-030 treatment of colon tumor cells increased intracellular cGMP levels and activated protein kinase G at concentrations that inhibit recombinant PDE10 and tumor cell growth. Inhibition of PDE10 by MCI-030 or siRNA increased the phosphorylation and degradation of β-catenin and inhibited Wnt-induced nuclear translocation to suppress TCF-mediated transcription of cyclin D and survivin, leading to cell cycle arrest and apoptosis. With attractive pharmacokinetics and ability to achieve high concentrations in colon mucosa following oral administration, MCI-030 was tested in the APC+/min-FCCC mouse model of colon tumorigenesis. At 7-8 weeks of age, mice endoscopically determined to be adenoma-free were assigned to receive either control or MCI-030 supplemented diet (1500ppm) for 14 weeks. MCI-030 reduced the multiplicity of colonic adenomas by 50% (control: 3.95 ± 0.81 vs. MCI-030: 1.95 ± 0.58, P < 0.05) and incidence by 36.7%. MCI-030 also reduced the multiplicity of polypoid adenomas (36%), microadenomas (69%), and flat adenomas (100%, P < 0.05). These data indicate that MCI-030 strongly inhibits tumorigenesis in a predictive preclinical mouse model of colorectal cancer without discernable toxicity and could be effective together with colonoscopy in humans to reduce polyp formation and prevent malignant progression. In addition, in vitro colony formation and transformation assays using human colon tumor cells showed benefits of combining MCI-030 with the ornithine decarboxylase inhibitor, DFMO, supporting testing of this novel combination in the APC+/min-FCCC mouse model as a strategy to further improve efficacy. Funding from NCI R01CA131378, R01CA148817, R01CA197147, and R01CA155638. Citation Format: Gary A. Piazza, Ashleigh Neese, Kevin Lee, Adam Keeton, Yulia Maxuitenko, Veronica Ramirez Alcantara, Kristy Berry, Jacob Valiyaveettil, Antonio Ward, Luciana Madeira da Silva, Jennifer Scalici, Bing Zhu, Tyler Mattox, Xi Chen, Margie Clapper, Harry Cooper, Wen-Chi Chang. Inhibition of a novel cancer target, PDE10, suppresses Wnt/β-catenin signaling and colon tumorigenesis: Benefits from combining with ornithine decarboxylase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1937.