Researchers at the University of Vermont have completed a first-in-human Phase I trial of a reformulated version of thiostrepton, a 70-year-old antibiotic repurposed to treat mesothelioma. The study, published in Nature Communications, found that the drug stabilized or reduced tumors in 67% of the 15 patients enrolled.
Targeting Mitochondrial Antioxidants in Mesothelioma
Mesothelioma, an aggressive cancer frequently linked to asbestos exposure, has historically lacked effective long-term treatment options. With an average survival rate of approximately 12 months, the disease presents a significant clinical challenge. The research team, led by University of Vermont associate professor Brian Cuniff, shifted the treatment paradigm by targeting the metabolic defenses that tumor cells use to survive.
“The goal was to take this drug called thiostrepton, which has been studied for 70 years, and formulate it in a way where it could be delivered to human beings for the first time ever, and use it as an anti-cancer drug.”
Clinical Trial Results and Safety Data
The Phase I trial enrolled 15 patients, primarily those with mesothelioma, though the study design allowed for a small subset of patients with metastatic lung and colorectal cancers. All participants shared the clinical phenotype of pleural effusions, a condition where fluid builds up between the lung and chest wall.
According to the findings, the drug was well-tolerated at a 90-milligram dose, with no deaths attributed to the treatment. The researchers reported that the drug provided disease control—meaning tumors either shrank or stopped growing—in 67% of participants. While standard-of-care chemotherapy for the disease remained largely unchanged for roughly three decades until the 2021 approval of an immunotherapy-based frontline regimen, this new approach demonstrated promising overall survival data in the small cohort.
Overcoming Historical Formulation Challenges
Thiostrepton has been known to scientists for decades, but its clinical application was previously blocked by its poor solubility and the complexity of manufacturing it to medical standards. The development team, working with the pharmaceutical firm RS Oncology, formulated the compound into a micellar solution. This allows for systemic delivery and, specifically, local administration directly into the chest cavity through catheters already used by patients to manage fluid buildup.
The researchers emphasize that this is not a traditional chemotherapy or immunotherapy. Instead, it functions as a cytotoxic immunomodulator
that targets the cancer’s energy production while sparing healthy cells, which are better able to tolerate PRX3 inhibition. UVM research scientist Victoria Gibson noted that when PRX3 was knocked out in animal models, there were no adverse effects, suggesting a favorable therapeutic window.
“The evidence — that you can knock out PRX3 in mice and there’s no adverse phenotype — supports our approach.”
Next Steps for Clinical Development
While the initial results are encouraging, the research team is looking ahead to broader applications. The current trial was conducted in the United Kingdom under the oversight of the Medicines and Healthcare products Regulatory Agency (MHRA). A completed Phase II study is expected to release a larger dataset later this year, which will provide more clarity on the drug’s efficacy across a wider patient base.
Beyond mesothelioma, the investigators remain interested in testing the drug’s effectiveness in other cancer types that exhibit similar metabolic stress profiles. As Cuniff noted, the team is actively exploring the potential for wider utilization as they move forward with development.
Find more reporting in our Health section.
Keep reading