Abstract 5322: The antitumor activity and immumodulatory effect of a novel phosphodiesterase 10 inhibitor

Abstract

Abstract Phosphodiesterase 10 (PDE10) is overexpressed in several types of cancer, including lung, breast and colon cancers. It has been proposed that inhibitors targeting PDE10 may exhibit antitumor activities. Previous studies have shown that PDE10 inhibition can selectively activate cGMP-dependent protein kinase to suppress oncogenic β-catenin signaling in colon cancer cells. However, the impact of PDE10 inhibitors on tumor cell immunogenicity has not been examined. Here we report the antitumor activity and immunomodulatory effect of a novel PDE10 inhibitor (ADT030) in preclinical models. We show that administration of ADT030 significantly inhibited the growth of murine colorectal cancer CT26. In a metastatic breast tumor model (4T1), ADT030 administration not only delayed the growth of the primary tumor but also reduced tumor metastasis, resulting in prolonged mouse survival. Immunological analysis revealed profound reduction of MDSCs in mice, and improved T cell tumor infiltration and function after ADT030 treatment. Moreover, the combination of ADT030 and anti-PD-1 antibody therapy led to further improved tumor growth control and mouse survival. These results implicate PDE10 as a promising therapeutic target and its inhibition may enhance the efficacy of cancer immunotherapy. Citation Format: Md Yeashin Gazi, Caitlin Brandle, Ogacheko Okoko, Xi Chen, Adam Keeton, Yulia Maxuitenko, Gary Piazza, Gang Zhou. The antitumor activity and immumodulatory effect of a novel phosphodiesterase 10 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5322.