Abstract B022: Effects of RSO-021 on cytokine profiles of malignant pleural effusions from patients enrolled in the MITOPE phase 1/2 clinical trial

Abstract

Abstract Tumor cells generate increased levels of reactive oxygen species (ROS) that promote growth and survival through activation of redox dependent signaling pathways. To survive under increased ROS levels tumor cells, including mesotheliomas, must increase antioxidant expression, activity and reliance on critical ROS scavenging pathways, including the mitochondrial peroxiredoxin 3 (PRX3) system. PRX3 is a critical 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. 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 mesothelioma (NCT05278975). RSO-021 is administered locally to patients through an indwelling pleural catheter (IPC) weekly. TS targets PRX3 in both adherent tumor cells and in non-adherent immune cell populations in a dose-dependent manner when tested ex vivo. Using MPE drainages from patients enrolled in the MITOPE trial we evaluated cytokine levels pre and 24 and 168 - hours (7 days) post initial administration of RSO-021. Cytokines were measured in decellularized MPE drainages using Human Cytokine ELISA plates manufactured by Signosis, Inc.Adiponectin and ICACM-1 where elevated in all patients pre and post treatment. Cytokines found to be increased in patients treated with RSO-021 included IL-1B, IL-8, and Resistin. Cytokines found to be decreased following treatment included IL-13, IL-31, and IP-10. Together, these data provide the first evidence for the molecular activity of TS in patients and the resulting changes to cytokine profiles. The downstream effects of these changes to cytokine levels on cellular composition and patient responses is an ongoing focus of our research teams. Citation Format: Terri Messier, Molly Scotland, George Naumov, Sean Dulloo, Dean Fennell, Brian Cunniff. Effects of RSO-021 on cytokine profiles of malignant pleural effusions from patients enrolled in the MITOPE phase 1/2 clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B022.