Mice lacking the enzyme develop and breed normally. That finding matters scientifically. Mitochondria perform essential jobs in nearly every cell, leading some researchers to doubt they could 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 Victoria Gibson, the study's lead author. "The evidence — that you can knock out PRX3 in mice and there's no adverse phenotype — supports our approach."

What did the trial find?

The phase 1 trial ran between 2022 and 2023 at sites in the United Kingdom under MHRA oversight, the UK's equivalent of the FDA. RS Oncology, a company spun out of UVM research, sponsored the study. Cunniff serves as the company's chief science officer.

Doctors delivered RSO-021 directly into the chest through a catheter that about 90 percent of mesothelioma patients already have in place to drain pleural effusions, fluid that builds between the lung and chest wall. Local delivery concentrates the drug near the tumor and reduces exposure elsewhere in the body.

Key results from the 15-patient cohort:

• Disease controlled in 67 percent of participants
• Tumors shrank in some patients
• Average progression-free survival: 4.2 months
• Overall survival better than standard treatment comparators
• 90-milligram dose met safety goals; no deaths attributed to the drug

Researchers also confirmed the drug hit its intended target in patient tissue — proof that what worked in cells and mice also happens in human tumors.

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

Could this work against other cancers?

Investigators detected signs of immune engagement, suggesting the drug may also help the body's defenses attack tumors. Cunniff described the dual mechanism in plain terms.

"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," he said.

The team is now designing second-generation PRX3 inhibitors with improved solubility. Future versions could potentially become oral tablets, which would broaden use beyond mesothelioma.

At UVM, Gibson is helping launch studies of thiostrepton in peritoneal cancers, including gastric and other gastrointestinal malignancies, with surgical oncologist Conor O'Neill.

"We believe this mechanism could be applicable to other cancers," Cunniff said.

What's next?

Phase 2 of the clinical trial has now finished. Researchers expect to present those results at a global oncology meeting later this year. The scientific groundwork began at UVM's Cancer Center around 2015, when Cunniff and collaborators first tested thiostrepton in mesothelioma cells.

For Gibson, the project has become personal. A family member once contacted the laboratory hoping to enroll a 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."

As a phase 1 trial, the study's main job was to test safety and find a workable dose. The survival signals — better than what doctors expect with standard care in a relapsed setting — warrant caution but also attention from oncologists.