Abstract 4144: Characterization of immune cell phenotypes in patient derived malignant pleural effusion treated with thiostrepton

Abstract

Abstract Tumor cells generate elevated levels of reactive oxygen species (ROS) and therefore exhibit increased expression, activity, and reliance on critical ROS scavenging pathways, including the mitochondrial peroxiredoxin 3 (PRX3) system. PRX3 is a critical reactive oxygen species (ROS) scavenging enzyme localized to the mitochondrial matrix. Our group has characterized the mechanism of action of the PRX3 inhibitor and pro-oxidant therapeutic thiostrepton (TS). TS covalently crosslinks the peroxidatic and resolving cysteines of PRX3, leading to increased levels of mitochondrial ROS, resulting in tumor cell death. We have characterized the cellular and chemical composition of malignant pleural effusion (MPE) from patients with advanced cancer and evaluated cellular responses to TS. TS targets PRX3 in both adherent tumor cells and in non-adherent immune cell populations in a dose-dependent manner. We further characterized MPE-infiltrated immune cells and cytokines released following TS-treatment. Together, these data provide the first evidence for the activity of TS in MPE and resulting changes to immune cell profiles. TS is the active pharmaceutical ingredient of RSO-021, a new covalent inhibitor of PRX3 currently being tested in the MITOPE phase 1/2 clinical trial in patients with malignant pleural effusion (MPE) due to advanced solid tumors or malignant mesothelioma (NCT05278975). Citation Format: Terri Messier, Roxana Del Rio Guerra, George Naumov, Brian Cunniff. Characterization of immune cell phenotypes in patient derived malignant pleural effusion treated with thiostrepton. [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 4144.