Targeting Mitochondrial PRX3 in Mesothelioma and Cancer

Researchers at the University of Vermont discovered a new vulnerability in mesothelioma, a rare and aggressive cancer linked to asbestos exposure, by targeting the tumor cell's energy metabolism and mitochondrial antioxidant defenses. In a phase one clinical trial, an experimental drug called RSO-021 achieved disease control in 67% of relapsed mesothelioma patients without causing treatment-related deaths. The scientific team, led by Professor Brian Cunniff and research scientist Victoria Gibson, challenged the traditional view of antioxidants by targeting peroxiredoxin 3 (PRX3), an enzyme that shields cancer cells from oxidative stress. By blocking PRX3 with a derivative of the natural antibiotic thiostrepton, toxic hydrogen peroxide accumulates within the mitochondria, selectively triggering cancer cell death while sparing normal tissue. Administered locally into the chest via an existing catheter for pleural effusions at a dose of 90 milligrams, RSO-021 demonstrated safety, tolerability, and target engagement in human tumors. Patients experienced a progression-free survival average of 4.2 months alongside extended overall survival, outperforming standard therapies and offering new hope for critically ill patients. The findings suggest broader applications beyond mesothelioma, with ongoing phase two trials and international collaborations exploring second-generation PRX3 inhibitors and oral formulations. Future research will also investigate these treatments for peritoneal, gastric, and other gastrointestinal tumors, potentially transforming cancer care through immunomodulatory and cytotoxic mechanisms.