Abstract 487: ITI-1020, a novel PDE type 1 inhibitor, reduces tumor growth in triple negative breast cancer (TNBC) mouse models

Abstract

Abstract Breast cancer is the most common cancer in women. Unfortunately, some patients do not benefit from most therapies and may even develop resistance to previously effective treatments leading to disease progression. Therefore, treatment resistance remains a significant challenge and new treatments are needed to overcome this problem. ITI-1020 is a potent and highly selective inhibitor of the phosphodiesterase 1 (PDE1) enzyme. Given the role of PDE1 in the regulation of essential cellular functions, including among others the transition of monocytes to macrophages and potentially the infiltration of macrophages into the tumor microenvironment (TME), we hypothesize that ITI-1020 will alter macrophage infiltration and polarization, as well as improve T cell function and recruitment into the TME, thereby promoting antitumor immunity in murine cancer models. We tested this hypothesis by studying the effect of ITI-1020 given, alone or in combination a PD-1 immune checkpoint inhibitor, on tumor growth, and TME composition of E0771 and 4T1 tumor-bearing mice, two syngeneic models of TNBC. Mice treated with ITI-1020 alone or in combination with anti-PD-1 antibody showed significant inhibition of tumor growth compared to isotype controls in both type of tumors. Flow cytometry analysis of the tumor microenvironment showed a significant shift in the polarization of macrophages toward a more inflammatory phenotype, and/or a reduction in the number of exhausted T cells. Furthermore, scRNAseq analysis of tumors from mice treated with ITI-1020 in monotherapy showed altered expression of genes involved in inflammatory processes and cell proliferation within the tumor microenvironment and in the cancer cells. These results suggest that ITI-1020 promotes antitumor immunity by a novel mechanism (PDE1 inhibition), leading to tumor growth inhibition in E0771 and 4T1 tumor models. Translating these findings to the clinic may provide a new hope for the treatment of refractory or resistant TNBC tumors. Citation Format: Maud Voisin, Aksinija A. Kogan, Stephen Goding, Gretchen L. Snyder, Robert E. Davis. ITI-1020, a novel PDE type 1 inhibitor, reduces tumor growth in triple negative breast cancer (TNBC) mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 487.