Mesothelioma is a rare and aggressive cancer that is often related to asbestos exposure. When asbestos fibers are inhaled, they can become trapped in the lungs, where they trigger chronic inflammation that can eventually lead to cancer decades later.
Every year, around 30,000 people worldwide are diagnosed with mesothelioma. Treatment options remain limited. Immunotherapy and chemotherapy can help some patients, but the disease remains extremely difficult to control. The patients, many of whom are men who previously worked in industries such as shipbuilding, oil refining and asbestos manufacturing, have a median survival of about 12 months. The five-year survival rate is about 10 percent.
“It is a disease that poses a significant unmet medical need,” says Brian Cunniff, a professor at the University of Vermont.
Now, research published in Nature Communications By Cunniff, UVM research scientist Victoria Gibson and an international team of collaborators describe an unusual strategy that could offer a new way to treat mesothelioma and potentially other forms of cancer.
In a phase one clinical trial sponsored by RS Oncology, LLC, patients with recurrent mesothelioma received an experimental drug that controlled disease progression in 67% of participants. Tumors also shrank in some patients. Overall, the drug was well tolerated and critically ill patients in the trial lived longer than patients receiving standard treatments.
Turning the cancer protective system into a weakness
Mesothelioma cells, like many cancer cells, produce unusually high levels of “reactive oxygen species,” unstable molecules that can damage cells. These molecules are generated in part because tumor cells have very active metabolisms.
To survive this stressful environment, cancer cells increase the production of antioxidant enzymes that help neutralize harmful molecules. One such enzyme is peroxiredoxin 3, or PRX3, which operates within mitochondria, the structures that produce much of a cell’s energy.
UVM researchers decided to reverse the usual logic behind antioxidant-based anti-cancer strategies.
For years, scientists tested whether increasing antioxidants could help fight cancer by reducing reactive oxygen species. Many of those clinical trials failed, and some research suggested that boosting antioxidants might actually help tumors grow.
Instead, the UVM team asked what would happen if cancer cells were deprived of one of their most important antioxidant defenses.
Their focus is on blocking PRX3. Without this protective enzyme, oxidative stress builds up within tumor cells until the damage becomes overwhelming.
An antibiotic that overloads tumor cells
The experimental treatment developed by RS Oncology arose from discoveries made at UVM. It uses thiostrepton, a natural antibiotic, to deactivate PRX3.
Blocking the enzyme causes hydrogen peroxide to accumulate within the mitochondria of tumor cells, eventually triggering cell death.
Cancer cells may be particularly vulnerable to this strategy because they already produce more reactive oxygen species than normal cells. PRX3 also regenerates more quickly in tumor cells, potentially allowing the treatment to target the cancer more selectively and have less effect on healthy tissue.
Laboratory experiments provided further evidence that PRX3 is important for mesothelioma survival.
When researchers completely removed PRX3 from mesothelioma tumor cell lines, mitochondrial function decreased, cell growth slowed dramatically, and cancer cells were no longer able to form tumors in animal experiments.
Other research groups have also shown that deletion of PRX3 in healthy mice does not produce adverse effects. That finding is important because mitochondria perform essential functions in almost all cells, leading some scientists to question whether they can be safely targeted.
“People will come up to us at conferences and tell us that you can’t target mitochondria because they’re too important,” Gibson said. “The evidence (that PRX3 can be inactivated in mice without producing an adverse phenotype) supports our approach.”
In other words, researchers have shown that mice can develop and function normally even when the genes responsible for producing PRX3 are deleted.
From a UVM laboratory to human patients
The scientific basis for the treatment began at the UVM Cancer Center around 2015.
After early experiments with thiostrepton produced encouraging results, the researchers helped establish RS Oncology, a private pharmaceutical company created to move UVM’s discoveries into clinical trials. Brian Cunniff, an associate professor in the Department of Pathology and Laboratory Medicine at the university’s Larner School of Medicine, serves as the company’s chief scientific officer.
The team eventually transformed thiostrepton into a clinical formulation called RSO-021.
Between 2022 and 2023, researchers tested RSO-021 in a phase one clinical trial in the United Kingdom. The study was conducted under the supervision of the MHRA, the British equivalent of the FDA.
The treatment is delivered directly into the chest through a catheter that many mesothelioma patients already have in place due to “pleural effusions,” a buildup of fluid in the space between the lung and the chest wall.
Approximately 90 percent of mesothelioma patients develop pleural effusions.
Delivering the drug locally allows doctors to concentrate it near the tumor while reducing the amount of drug circulating to the rest of the body.
Initial trial shows encouraging survival results
The phase one study met its safety and tolerability goals at a 90 milligram dose, and no patient deaths were attributed to the drug.
The researchers also found evidence in the patient’s tissue that RSO-021 was reaching its intended biological target. That result confirmed that the mechanism previously observed in cells and mice was also occurring in human tumors.
The median progression-free survival was 4.2 months, approximately comparable to existing treatments.
The researchers were most encouraged by the overall survival. Among the 15 patients in the cohort, survival was better than typically seen with currently available therapies. Cunniff described the find as a potential “game changer.”
“Our overall survival data are very promising and we expect this to persist with additional patients,” Cunniff said.
The findings also suggest that RSO-021 may do more than directly kill cancer cells. It may also alter the immune environment around the tumor in a way that helps the immune system attack or slow down the cancer.
“Our drug has cytotoxic activity, it can kill tumor cells, but it also has immunomodulatory capacity, so it can modulate the immune system to control the tumor,” Cunniff said.
The second phase of the clinical trial has already been completed. The researchers hope to present the results at a global oncology meeting this year.
Expanding the strategy beyond mesothelioma
The research is now advancing in several directions.
Scientists at UVM and RS Oncology, in collaboration with the University of Leicester and other UK institutions, are developing second-generation PRX3 inhibitors with improved solubility.
Future versions could be taken in oral tablet form, which could make the treatment easier to administer and potentially expand its use beyond mesothelioma.
At UVM, Gibson, lead author of the new study, continues his work as a postdoctoral researcher. She is helping to initiate research investigating thiostrepton in peritoneal malignancies, including mesothelioma, gastric cancer, and other gastrointestinal cancers.
That work is being done in collaboration with Conor O’Neill, a surgical oncologist at the UVM Cancer Center and UVM Health.
“We think this mechanism could be applicable to other cancers,” Cunniff said.
For Gibson, watching research move from laboratory experiments to human trials has given the project a deeply personal dimension.
“I’ve always had a desire to help people because I feel like everyone has experienced cancer in their life, whether it’s themselves, friends or family,” she said.
Still, she was surprised when a family member contacted the lab hoping to enroll her dying father in the clinical trial.
“We just work in a lab all day working with cells,” he recalled, “and the fact that we’re having an impact on people, that they want to participate in this clinical trial, was just amazing to me.”