Thiostrepton-derived RSO-021 achieves 67% disease control in relapsed mesothelioma patients via mitochondrial PRX3 inhibition.

Aggressive malignancies like mesothelioma present significant therapeutic challenges, especially in relapsed or refractory settings, with limited treatment options. Cancer cells often upregulate antioxidant networks to counteract oxidative stress and promote survival. Peroxiredoxin 3 (PRX3), a key mitochondrial antioxidant enzyme, plays a critical role in regulating reactive oxygen species (ROS) homeostasis within tumor cells. Targeting this specific mitochondrial vulnerability offers a novel strategy to disrupt tumor redox balance and induce selective cancer cell death.

Researchers first demonstrated that genetic deletion of PRX3 impaired mitochondrial bioenergetics and suppressed mesothelioma growth in preclinical models. They then tested pharmacological inhibition using thiostrepton (TS), which induces apoptosis in patient-derived mesothelioma explants. This led to a Phase 1 clinical trial (NCT05278975) in patients with relapsed pleural mesothelioma and malignant pleural effusion. Patients received weekly local intrapleural treatment with the TS-formulated drug product RSO-021 at 90 mg. Primary endpoints were safety, tolerability, and dose finding, with secondary endpoints exploring pharmacokinetics, objective response rate, disease control rate, and progression-free survival.

Preclinically, genetic deletion of PRX3 significantly impaired mitochondrial bioenergetics and suppressed mesothelioma growth. Pharmacological inhibition of PRX3 with thiostrepton induced apoptosis in patient-derived mesothelioma explants. In the Phase 1 trial, weekly local intrapleural treatment with RSO-021 at 90 mg was well tolerated, meeting primary safety and tolerability endpoints. The treatment led to disease control in 67% of patients at 12 weeks, and was associated with observed tumor reductions. Genomic screening identified Solute Carrier Family 7 member 11 (SLC7A11) as a mediator of TS resistance. This suggests that combining SLC7A11 targeting with RSO-021 could further enhance its pro-oxidant activity and overcome potential resistance mechanisms. The study successfully met its primary endpoints of safety, tolerability, and dose finding. Secondary endpoints, including objective response rate and progression-free survival, were explored, indicating promising early efficacy signals.

RSO-021 achieved disease control in 67% of relapsed pleural mesothelioma patients at 12 weeks.