New Drug RSO-021 Shows Promise in Mesothelioma Trial by Targeting Cancer's Energy System
核心洞察
A phase one clinical trial found that RSO-021 controlled disease progression in 67% of patients with relapsed mesothelioma (搜索), with some patients experiencing tumor shrinkage.
The drug disables the antioxidant enzyme peroxiredoxin 3 (搜索) (PRX3 (搜索)) in tumor cell mitochondria, causing a buildup of hydrogen peroxide that selectively kills cancer cells.
Overall survival in the 15-patient cohort exceeded that seen with standard treatments, and the drug was well tolerated with no patient deaths attributed to it.
A new drug developed from University of Vermont research has demonstrated significant promise against mesothelioma (搜索), a rare and aggressive cancer with few effective treatment options. In a phase one clinical trial, the drug RSO-021 controlled disease progression in 67% of patients with relapsed mesothelioma, and in some patients tumors actually shrank, according to a study published July 14 in Nature Communications.
Mesothelioma (搜索), usually caused by asbestos exposure, affects approximately 30,000 people worldwide each year. Current treatments — immunotherapy and chemotherapy — offer limited benefit. Patients face a median survival of approximately 12 months and a five-year survival rate of around 10 percent.
"It's a disease of a significant unmet medical need," said Brian Cunniff, associate professor of pathology and laboratory medicine at UVM's Larner College of Medicine and chief science officer of RS Oncology (搜索).
A Counterintuitive Mechanism of Action
The drug takes an unconventional approach to fighting cancer. Like many cancers, mesothelioma (搜索) tumors generate elevated levels of reactive oxygen species — unstable, damaging molecules that are a byproduct of rapid tumor cell metabolism. To survive, tumor cells ramp up production of antioxidant enzymes, including peroxiredoxin 3 (搜索) (PRX3 (搜索)), located in the mitochondria.
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 actually promoted tumor growth. The UVM team took the opposite approach: inhibit PRX3 (搜索), overwhelm the tumor cell with oxidative stress, and kill it.
RSO-021, developed by RS Oncology (搜索) based on UVM's discoveries, uses a naturally occurring antibiotic called thiostrepton to disable PRX3 (搜索). 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, increasing selectivity to cancer cells rather than healthy ones.
When the team deleted PRX3 (搜索) entirely in mesothelioma (搜索) tumor cell lines, mitochondrial function decreased, cell proliferation slowed dramatically, and the cancer cells were unable to form tumors in animal tests. Other groups have shown that knocking out PRX3 in healthy mice produced no adverse effects. "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, UVM research scientist and lead author on the study. "The evidence — that you can knock out PRX3 in mice and there's no adverse phenotype — supports our approach."
From Laboratory to Clinic
The laboratory foundation for this work was established at UVM's Cancer Center around 2015. 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 (搜索) patients. This local delivery concentrates the drug at the tumor site while limiting systemic exposure.
The phase one trial, conducted in the United Kingdom under oversight of the MHRA between 2022 and 2023, 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 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 drug may 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," Cunniff explained.
What Comes Next
Phase two of the drug trial has now been completed, and results are expected to be presented at a global oncology meeting later this year. The research program is expanding on multiple fronts. The UVM and RS Oncology (搜索) team, in collaboration with the University of Leicester and other UK institutions, are developing second-generation PRX3 (搜索) 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 (搜索).
At UVM, Gibson is remaining as a postdoctoral researcher to help initiate new research using thiostrepton for peritoneal malignancies, including mesothelioma (搜索), gastric cancer, and other gastrointestinal cancers, in collaboration with Conor O'Neill, a surgical oncologist at the UVM Cancer Center. "We believe this mechanism could be applicable to other cancers," Cunniff said.
For Gibson, the work carries personal meaning. "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. 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, 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."