Abstract 1768: A novel PDE10 inhibitor suppresses tumor growth in an orthotopic mouse model of lung cancer

Abstract

Abstract Background: Conventional chemotherapy and radiation cannot distinguish between cancer and normal cells resulting in dose-limiting toxicity. Molecular targeted drugs hold greater promise, but few targets are unique to cancer cells and drugable. Our laboratory discovered that the cyclic nucleotide phosphodiesterase, PDE10, is elevated in human lung tumor cells and essential for their growth. A novel PDE10 inhibitor, MCI-020 was designed to achieve high lung concentrations and found to selectively inhibit the growth of human lung tumor cells in vitro. Objective: Evaluate pharmacokinetics, tissue distribution and antitumor efficacy of MCI-020 in mice. Material and Methods: MCI-020 (100 mg/kg) was formulated as a suspension and administrated orally to C57BL/6 female mice. Free levels of MCI-020 were quantified in plasma and tissues by reverse-phase chromatography with tandem mass spectrometry detection. For efficacy evaluation, athymic nude-Foxn1nu female mice were treated with MCI-020 (150 mg/kg bid) for 5 days before inoculation with 1x106 A549 cells/mouse into the left lung. After inoculation, MCI-020 treatment continued for 4 weeks. Anti-tumor efficacy of MCI-020 was evaluated by gross and histological grading of the lungs. Results: MCI-020 displayed attractive oral bioavailability and reached appreciably higher concentrations in lungs compared with plasma. MCI-020 treatment showed strong anti-tumor efficacy in the orthotopic mouse model of lung cancer and was well tolerated. Compared with the vehicle group in which 85% of the mice formed lung tumors, only 25% of the mice in the treatment group developed tumors. Histological grading of the extent of tumor formation revealed a score of 0.83 ± 0.3 (low involvement) for the treatment group, compared with 2.6 ± 0.4 (high involvement) for the vehicle group. Conclusions: These observations support a critical role of PDE10 in lung tumor growth and suggest that PDE10 inhibitors will be useful for the prevention or treatment of lung cancer. This project is supported by NIH grant 1R01CA148817. Citation Format: Veronica Ramirez-Alcantara, Michele A. Schuler, Bing Zhu, Nan Li, Evrim Gurpinar, Joshua Canzoneri, Adam Keeton, Bernard Gary, Suzanne Russo, Lori Coward, Gregory S. Gorman, William Grizzle, Xi Chen, Gary A. Piazza. A novel PDE10 inhibitor suppresses tumor growth in an orthotopic mouse model of lung cancer. [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 1768. doi:10.1158/1538-7445.AM2014-1768