| Popis: |
Previous research suggests that the antineoplastic activity of sulindac is mediated by a cyclooxygenase (COX) independent mechanism involving dual inhibition of RAS and β-catenin signaling. ADT030 is a novel non-COX inhibitory sulindac-derivative designed to target RAS and phosphodiesterase 10 (PDE10) to block MAPK/AKT signaling and activate cGMP/PKG signaling to suppress oncogenic β-catenin transcription, respectively. ADT-030 potently and selectively inhibits growth and induces apoptosis of a variety of cancer cell lines and has robust antitumor activity in multiple mouse tumor models by oral administration. However, the impact of ADT-030 on the tumor microenvironment (TME) has not been examined. Here we report the antitumor activity and immunomodulatory effect of ADT-030 in preclinical models. We show that oral administration of ADT030 significantly inhibited the growth of multiple types of murine tumors in immunocompetent mice. In a metastatic breast tumor model (4T1), ADT-030 not only delayed the growth of the primary tumor but also reduced tumor metastasis, leading to improved mouse survival. Immunological analysis revealed marked reduction of MDSCs in mice, and increased T cell tumor infiltration after ADT-030 treatment. The antitumor activity of ADT030 was diminished in immunodeficient mice or immunocompetent mice depleted of CD8+ T cells, suggesting the dependence of ADT-030 on host immunity. Moreover, the combination of ADT-030 and anti-PD-1 antibody therapy led to further improved tumor growth control and mouse survival. Bulk and single-cell RNAseq is being conducted to determine the impact of ADT-030 on the cell compositions and transcriptomic changes in the TME. Altogether, our study provides insight into the mechanism of action of ADT-030 and underscores the potential of ADT-030 as a monotherapy or in combination with immunotherapies for RAS and Wnt/β-catenin driven cancers. Citation Format: Md Yeashin Gazi, Ogacheko Okoko, Xin Wang, Caitlin Brandle, Zhi-chun Ding, Amit Mitra, Veronica Ramirez-Alcantara, Xi Chen, Adam Keeton, Yulia Maxuitenko, Gary Piazza, Gang Zhou. A novel dual-acting RAS/β-catenin inhibitor activates antitumor immunity to potentiate cancer immunotherapy [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 478. |
