Abstract 1762: Phosphodiesterase 10, a novel target for colorectal cancer therapeutics

Abstract

Abstract Phosphodiesterase 10 (PDE10) is a newly characterized PDE isozyme that is expressed in regions of the brain affecting cognition and psychomotor activity. Inhibitors are currently being developed for the treatment of schizophrenia and Huntington's disease, one of which, Pf-2545920 (MP-10), is in clinical trials. Although PDE10 is not expressed in most peripheral tissues, we recently found high levels in colon tumor cells compared with normal colonocytes and that genetic silencing by siRNA selectively suppressed colon tumor cell growth. These observations suggest that PDE10 may represent a novel anticancer target. Pf-2545920 was found to selectively inhibit colon tumor cell growth. Here we show that PDE10 knockdown reduced the sensitivity of colon tumor cells to Pf-2545920. Consistent with the ability of PDE10 to degrade cGMP and cAMP, Pf-2545920 activated both PKG and PKA as determined using site-specific phospho-VASP antibodies. Treatment of colon tumor cells with Pf-2545920 induced caspase activation as well as cytotoxicity. A novel PDE10 inhibitor, MCI-030, was found to potently inhibit colon tumor cell lines with IC50 values in the 0.3μM range without significantly affecting the growth of normal colonocytes. MCI-030 appears to exhibit selectivity for cGMP PDE10 signaling over cAMP shown by the activation of PKG but not PKA at doses that match those which inhibit growth. PDE10 knockdown cells were appreciably less sensitive to MCI-030 as well. These findings support a novel role of PDE10 as a therapeutic target for the treatment or prevention of colorectal cancer. Citation Format: Kevin J. Lee, Nan Li, Xi Chen, Bing Zhu, Larry Yet, Gary Piazza. Phosphodiesterase 10, a novel target for colorectal cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1762. doi:10.1158/1538-7445.AM2014-1762