Study reports a counterintuitive new approach to treating mesothelioma

Mesothelioma is a rare but aggressive cancer, usually caused by exposure to asbestos. Inhaled asbestos fibers become lodged in the lungs, causing inflammation that can lead to tumor formation decades later. Worldwide, about 30,000 people are diagnosed with mesothelioma each year. Current treatments-immunotherapy and chemotherapy-offer limited benefit. Patients-often men who worked in shipbuilding, oil refining, and asbestos manufacturing-face a median survival of approximately 12 months and a five-year survival rate around 10 percent. 

 It's a disease of a significant unmet medical need."

Brian Cunniff, Professor, University of Vermont

Now, a study published July 14 in Nature Communications by Cunniff, UVM research scientist Victoria Gibson, and an international team of collaborators reports a counterintuitive new approach to treating the disease-and perhaps other cancers too.

In a "phase one" clinical trial, sponsored by RS Oncology, LLC, people with relapsed mesothelioma were given the new drug and it controlled disease progression in 67% of the patients and in some patients the tumors got smaller. More importantly, the drug was well tolerated and these critically ill patients lived longer than patients given the standard treatments.

Turning cancer's own defenses against it

Like many cancers, mesothelioma tumors generate elevated levels of "reactive oxygen species"-unstable and damaging molecules that are a byproduct of rapid tumor cell metabolism. To survive under these conditions, tumor cells ramp up production of antioxidant enzymes, including one called peroxiredoxin 3, or PRX3, in the cell's powerhouses-the mitochondria-that protect tumor cells from these damaging molecules.

The UVM team's insight was to flip the conventional logic of cancer treatment. For years, clinical trials attempted to increase antioxidants to combat cancer, reasoning that lowering reactive oxygen species would slow tumor growth. Those trials largely failed, and some showed that increasing antioxidants promoted tumor growth. The UVM team took the opposite approach: inhibit PRX3, overwhelm the tumor cell with oxidative stress, and kill it.

The trial drug developed by RS Oncology, based on UVM's discoveries, uses a naturally occurring antibiotic, thiostrepton, to disable PRX3. This causes a buildup of hydrogen peroxide in the mitochondria of tumor cells and triggers their death. Because tumor cells generate more reactive oxygen species than normal cells, PRX3 turns over faster in tumor cells which increases selectivity to cancer cells rather than healthy ones.

When the team deleted PRX3 entirely in mesothelioma tumor cell lines, the results were striking: mitochondrial function decreased, cell proliferation slowed dramatically, and the cancer cells were unable to form tumors in animal tests. Other groups have shown that when PRX3 is knocked out in healthy mice, there were no adverse effects-a finding that addresses a common objection to targeting mitochondria. "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, the scientists showed that they could remove the genes for the PRX3 enzyme from developing mice and that the animals functioned normally.

From the laboratory to the clinic

The laboratory foundation for this work was established at UVM's Cancer Center around 2015. Seeing promising early results with thiostrepton, a team formed RS Oncology, a private pharmaceutical company, to translate UVM findings into the clinic. UVM's 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. Eventually, the team developed thiostrepton into a novel clinical formulation called RSO-021 and conducted a phase one clinical trial in the United Kingdom under oversight of the MHRA, the UK equivalent of the FDA, between 2022 and 2023.

The drug is administered directly into the chest through a catheter already in place for patients who have "pleural effusions"-a buildup of fluid between the lung and chest wall that affects approximately 90 percent of mesothelioma patients. This local delivery concentrates the drug at the tumor site while limiting systemic exposure.

The phase one trial met its requirements for safety and tolerability at a 90-milligram dose, with no patient deaths attributed to the drug. Crucially, the team demonstrated on-target engagement in patient tissue samples-confirming that the drug's mechanism of action, observed in cells and mice in the laboratory, also works in human tumors.

Progression-free survival averaged 4.2 months, comparable to current therapies. More significantly, overall survival in the cohort of 15 patients was better than what is seen with existing treatments-a finding Cunniff describes as a potential "game changer."

"Our overall survival data is very promising and will hopefully persist with additional patients," Cunniff said.

The team's data also suggests the new drug may also help awaken the immune system to attack or slow the tumor. "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 drug trial has now been completed, and results are expected to be presented at a global oncology meeting this year. 

What comes next

The research program is expanding on multiple fronts. The UVM and RS Oncology team, in collaboration with the University of Leicester and other institutions in the UK, are developing second-generation PRX3 inhibitors that are more soluble and potentially deliverable as an oral tablet. This might allow the drug to be brought to market more easily and have application with cancer types beyond mesothelioma. At UVM, Victoria Gibson, the lead author on the new study, is remaining as a postdoctoral researcher to help initiate new research using thiostrepton for peritoneal malignancies, including mesothelioma, gastric cancer, and other gastrointestinal cancers, 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, the work is personal. "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. Still, when a family member called the lab hoping to enroll her dying father in the clinical trial, Gibson was caught off guard. "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."