Mesothelioma is a rare and aggressive cancer that is most often linked to asbestos exposure. When asbestos fibers are inhaled, they can become trapped in the lungs, where they trigger chronic inflammation that may eventually lead to cancer decades later.
About 30,000 people worldwide are diagnosed with mesothelioma every year. Treatment options remain limited. Immunotherapy and chemotherapy can help some patients, but the disease is still extremely difficult to control. 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 approximately 10 percent.
“It’s a disease of 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 describes 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 relapsed mesothelioma received an experimental drug that controlled disease progression in 67% of participants. Tumors also shrank in some patients. The drug was generally well tolerated, and the critically ill patients in the trial lived longer than patients receiving standard treatments.
Turning Cancer’s 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 highly active metabolisms.
To survive that stressful environment, cancer cells increase production of antioxidant enzymes that help neutralize the damaging molecules. One of those enzymes is peroxiredoxin 3, or PRX3, which operates inside mitochondria, the structures that produce much of a cell’s energy.
The UVM researchers decided to reverse the usual logic behind antioxidant-based 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 could actually help tumors grow.
The UVM team instead asked what would happen if cancer cells were deprived of one of their most important antioxidant defenses.
Their approach focuses on blocking PRX3. Without this protective enzyme, oxidative stress builds inside tumor cells until the damage becomes overwhelming.
An Antibiotic That Overloads Tumor Cells
The experimental treatment developed by RS Oncology grew out of discoveries made at UVM. It uses thiostrepton, a naturally occurring antibiotic, to disable PRX3.
Blocking the enzyme causes hydrogen peroxide to accumulate inside 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 turns over more rapidly in tumor cells, potentially allowing the treatment to target cancer more selectively while having less effect on healthy tissue.
Laboratory experiments provided further evidence that PRX3 is important for mesothelioma survival.
When researchers completely deleted PRX3 from mesothelioma tumor cell lines, mitochondrial function declined, cell growth slowed sharply, and the cancer cells could no longer form tumors in animal experiments.
Other research groups have also shown that eliminating PRX3 in healthy mice does not produce adverse effects. That finding is important because mitochondria perform essential functions in nearly every cell, leading some scientists to question whether they can be safely targeted.
“People will come up to us at conferences and state that you can’t target the mitochondria because they’re too important,” said Gibson. “The evidence — that you can knock out PRX3 in mice and there’s no 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 removed.
From a UVM Laboratory to Human Patients
The scientific groundwork for the treatment began at UVM’s Cancer Center around 2015.
After early experiments with thiostrepton produced encouraging results, researchers helped establish RS Oncology, a private pharmaceutical company created to move the UVM discoveries toward clinical testing. Brian Cunniff, an associate professor in the Department of Pathology and Laboratory Medicine at the university’s Larner College of Medicine, serves as the company’s chief science 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 oversight of the MHRA, the UK equivalent of the FDA.
The treatment is delivered directly into the chest through a catheter that many mesothelioma patients already have in place because of “pleural effusions,” a buildup of fluid in the space between the lung and 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 medication circulating throughout the rest of the body.
Early Trial Shows Encouraging Survival Results
The phase one study met its safety and tolerability goals at a dose of 90 milligrams, and no patient deaths were attributed to the drug.
Researchers also found evidence in patient tissue that RSO-021 was hitting its intended biological target. That result confirmed that the mechanism previously observed in cells and mice was also occurring in human tumors.
Average progression-free survival was 4.2 months, roughly comparable to existing treatments.
The researchers were more encouraged by overall survival. Among the 15 patients in the cohort, survival was better than what is typically seen with currently available therapies. Cunniff described the finding as a potential “game changer.”
“Our overall survival data is very promising and will hopefully 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 restrain the cancer.
“Our drug has both cytotoxic activity, it can kill the tumor cells, but it also has immunomodulatory capacity where it can modulate the immune system to now manage the tumor,” said Cunniff.
Phase two of the clinical trial has now been completed. The researchers expect to present the results at a global oncology meeting this year.
Expanding the Strategy Beyond Mesothelioma
The research is now moving in several directions.
Scientists from UVM and RS Oncology, working with the University of Leicester and other institutions in the UK, are developing second-generation PRX3 inhibitors with improved solubility.
Future versions could potentially be taken as an oral tablet, which could make the treatment easier to administer and potentially broaden its use beyond mesothelioma.
At UVM, Gibson, the lead author of the new study, is continuing the work as a postdoctoral researcher. She is helping launch research investigating thiostrepton in peritoneal malignancies, including mesothelioma, gastric cancer, and other gastrointestinal cancers.
That work is being conducted in collaboration with Conor O’Neill, a surgical oncologist at the UVM Cancer Center and UVM Health.
“We believe this mechanism could be applicable to other cancers,” Cunniff said.
For Gibson, seeing the research move from laboratory experiments into human trials has given the project a deeply personal dimension.
“I’ve always just had a desire to help people because I feel like everyone has experienced cancer in their life, whether it’s them, friends, or family members,” she said.
Even so, she was surprised when a family member contacted the laboratory hoping to enroll her dying father in the clinical trial.
“We just work in a lab all day working with cells,” she recalled, “and the fact that we’re making an impact on people, that they’re wanting to be on this clinical trial, just was amazing to me.”
