Experimental drug RSO-021 controls mesothelioma progression in 67% of patients

An experimental mesothelioma drug called RSO-021 controlled disease progression in 67% of patients in a Phase 1 trial, according to results published in Nature Communications and detailed by researchers at the University of Vermont. The 15-person trial, run in the United Kingdom between 2022 and 2023, recorded an average progression-free survival of 4.2 months in a cancer where treatment options have historically been limited and short-lived.

The drug works by disabling PRX3, an antioxidant enzyme that protects mitochondria inside tumor cells, rather than attacking DNA the way most chemotherapies do. Disrupting PRX3 lets oxidative stress build up inside the cancer cell until it dies, a mechanism the University of Vermont team has spent years developing before it reached human testing.

Disabling PRX3 Inside Mitochondria

Brian Cunniff, an associate professor of pathology and laboratory medicine at the University of Vermont’s Larner College of Medicine and chief science officer at RS Oncology, has been studying PRX3 for most of his research career. “It’s a disease of a significant unmet medical need,” Cunniff said of mesothelioma, a rare, aggressive cancer usually tied to asbestos exposure that is often diagnosed too late for surgery to help. Victoria Gibson, the UVM research scientist who led the study described in the new paper, said the mitochondria-targeting approach was widely doubted before the lab’s results came in. Other scientists have repeatedly told her, at conferences and elsewhere, that mitochondria are too essential to cellular survival to target safely, pushback Gibson said reflected a worry that the drug would damage healthy cells along with cancerous ones, according to details reported by ScienceDaily.

Results From the UK Phase 1 Trial

The trial enrolled 15 patients with relapsed malignant pleural mesothelioma, all of whom had already exhausted standard treatments, and was overseen by the United Kingdom’s Medicines and Healthcare products Regulatory Agency, according to details the University of Vermont published on its own site. Disease control, meaning the cancer neither grew nor spread further under treatment, held in 67% of those patients. No deaths were attributed to the drug itself, and the trial met its safety and tolerability goals at a 90-milligram dose, clearing the bar Phase 1 studies are designed to test before a drug moves further.

“[The] overall survival data is very promising and will hopefully persist with additional patients,” Cunniff said, a note of caution built into the sentence itself: 15 patients is a small enough sample that individual outliers can swing an average, and the team has said the finding needs to hold up in a larger group before it means much for the broader mesothelioma population.

A Catheter, Not a Pill, For Now

RSO-021, formulated from the naturally occurring antibiotic thiostrepton, was delivered directly into the chest cavity through a catheter rather than taken as a pill or infused into the bloodstream, a delivery method suited to mesothelioma’s tendency to spread across the lining of the lungs rather than form a single tumor mass. Cunniff described the compound’s effect as twofold: “[The] drug has both cytotoxic activity, it can kill the tumor cells, but it also has immunomodulatory capacity,” he said, meaning it may also help the immune system recognize and attack cancer cells beyond the ones it kills directly. Researchers examined tissue from trial patients afterward and found direct evidence the drug had reached and disrupted PRX3 inside human tumors, not just in the lab models that first suggested the approach could work.

The Path to a Phase 2 Readout

RS Oncology, the drug’s sponsor, has since moved RSO-021 into a Phase 2 study registered as NCT05278975 on ClinicalTrials.gov under the name MITOPE, expanding testing to malignant pleural effusion and metastatic disease to the lung beyond mesothelioma alone. The company announced dosing its first Phase 2 patient before the Nature Communications paper detailing the Phase 1 results was released.

Alongside the clinical work, the University of Vermont team is developing a second-generation version of the drug with University of Leicester collaborators, aimed at improving its solubility enough to eventually be taken as an oral tablet instead of delivered by catheter, and at extending the approach to peritoneal cancers affecting the stomach and gastrointestinal tract. Gibson, who has continued the research as a postdoctoral scientist, described the work as motivated by something simple: nearly everyone, in her experience, has been touched by cancer in some way, whether as a patient or through someone close to them.

Conor O’Neill, a surgical oncologist at the UVM Cancer Center who was not part of the drug’s development but treats mesothelioma patients directly, has pointed to the disease’s grim baseline as the reason even a small, uncontrolled Phase 1 result draws attention: most patients with relapsed mesothelioma have few options left once standard chemotherapy stops working. Whether RSO-021’s 67% disease-control rate translates into a longer-term survival advantage, and for how many patients, is the question the ongoing Phase 2 trial is now designed to answer.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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