University of Vermont researchers developed RSO-021, an experimental drug targeting mesothelioma by disabling the antioxidant enzyme peroxiredoxin 3 (PRX3) in cancer cell mitochondria. In a phase one trial of 15 patients, RSO-021 was well tolerated and controlled disease progression in 67% of participants. By blocking PRX3, the drug causes toxic hydrogen peroxide to accumulate, triggering cancer cell death. Researchers are now developing oral formulations and expanding the therapy to other cancers.
RSO-021 phase one trial results
- ▪In a phase one clinical trial sponsored by RS Oncology, LLC, the experimental drug RSO-021 controlled disease progression in 67% of patients with relapsed mesothelioma.
- ▪The phase one trial of RSO-021 met its safety and tolerability goals at a 90-milligram dose, with no patient deaths attributed to the drug.
- ▪The phase one clinical trial of RSO-021 was conducted in the United Kingdom between 2022 and 2023 under the oversight of the MHRA.
- ▪In the phase one trial of RSO-021, the 15-patient cohort achieved an average progression-free survival of 4.2 months and showed improved overall survival compared to standard therapies.
PRX3 inhibition mechanism
- ▪Research showed that healthy mice lacking the genes to produce peroxiredoxin 3 developed and functioned normally without experiencing adverse effects.
- ▪Disabling peroxiredoxin 3 causes hydrogen peroxide to accumulate inside tumor cell mitochondria, triggering cell death by overwhelming the cells with oxidative stress.
- ▪Laboratory experiments deleting peroxiredoxin 3 from mesothelioma cell lines resulted in declined mitochondrial function, slowed cell growth, and an inability to form tumors in animals.
- ▪The experimental drug RSO-021 uses thiostrepton, a naturally occurring antibiotic, to disable the antioxidant enzyme peroxiredoxin 3 inside the mitochondria of cancer cells.
Mesothelioma disease characteristics
- ▪Approximately 30,000 people worldwide are diagnosed annually with mesothelioma, which has a median survival of 12 months and a 10% five-year survival rate.
- ▪Mesothelioma is a rare, aggressive cancer linked to asbestos exposure that triggers chronic lung inflammation, which can lead to cancer decades later.
- ▪Approximately 90% of mesothelioma patients develop pleural effusions, which is a buildup of fluid in the space between the lung and chest wall.
UVM research to clinical translation
- ▪University of Vermont researchers helped establish RS Oncology, LLC to transition their laboratory discoveries into clinical trials, with Brian Cunniff serving as chief science officer.
- ▪RSO-021 is administered directly into the chest via a catheter, concentrating the drug near the tumor while minimizing its circulation throughout the rest of the body.
- ▪The scientific groundwork for RSO-021 began around 2015 at the University of Vermont Cancer Center, led by researchers Brian Cunniff and Victoria Gibson.
Second-generation PRX3 inhibitors
- ▪Future second-generation peroxiredoxin 3 inhibitors are being designed as oral tablets to simplify administration and expand treatment options beyond mesothelioma.
- ▪Scientists from the University of Vermont, RS Oncology, and the University of Leicester are developing second-generation peroxiredoxin 3 inhibitors with improved solubility.
Peritoneal malignancy applications
- ▪The research on peritoneal malignancies is conducted in collaboration with Conor O'Neill, a surgical oncologist at the University of Vermont Cancer Center and University of Vermont Health.
- ▪University of Vermont researcher Victoria Gibson is launching studies to investigate the antibiotic thiostrepton in peritoneal malignancies, including gastric and gastrointestinal cancers.
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