By Budi Oetomo Narendra 
Mesothelioma, a rare and exceptionally aggressive cancer, is predominantly linked to occupational or environmental exposure to asbestos fibers. When these microscopic fibers are inhaled, they can become lodged in the delicate lining of the lungs, abdomen, or heart, initiating a chronic inflammatory process that, over decades, can culminate in malignant transformation. This insidious latency period, often spanning 20 to 50 years, makes early diagnosis challenging and contributes to the advanced stage at which the disease is typically identified. Globally, approximately 30,000 individuals are diagnosed with mesothelioma annually, a number that belies the profound impact of this devastating illness on patients and their families.
The Persistent Challenge of Mesothelioma
The prognosis for mesothelioma patients remains starkly grim, reflecting a significant unmet medical need. Current treatment modalities, including surgery, chemotherapy, and immunotherapy, offer limited efficacy. While certain combinations of immunotherapy, such as nivolumab plus ipilimumab, or chemotherapy regimens like pemetrexed and cisplatin, have shown modest improvements in survival, the disease is notoriously resistant to conventional therapies. The median survival for patients, many of whom are men with a history of employment in high-risk industries like shipbuilding, oil refining, and asbestos manufacturing, hovers around a mere 12 months. The five-year survival rate remains distressingly low, at approximately 10 percent, underscoring the urgent necessity for innovative therapeutic approaches.
"It’s a disease of a significant unmet medical need," emphasizes Brian Cunniff, a distinguished professor at the University of Vermont (UVM) and a leading figure in this research. His sentiment resonates deeply within the oncology community, where the search for effective mesothelioma treatments has been a long and arduous journey.
A Paradigm Shift in Cancer Therapy
However, a beacon of hope has emerged from recent research. A groundbreaking study published in the prestigious journal Nature Communications by Professor Cunniff, UVM research scientist Victoria Gibson, and an international consortium of collaborators, details an unconventional strategy that could revolutionize the treatment landscape for mesothelioma and potentially other forms of cancer. Their approach represents a fundamental re-evaluation of how cellular metabolism can be exploited to selectively target malignant cells.
The research culminated in a phase one clinical trial, sponsored by RS Oncology, LLC, where patients suffering from relapsed mesothelioma received an experimental drug. The results were remarkably encouraging: disease progression was controlled in 67% of participants, with some patients also exhibiting measurable tumor shrinkage. Critically, the drug was generally well-tolerated, and the critically ill patient cohort in the trial demonstrated improved survival outcomes compared to those typically observed with standard treatments. This early success has ignited cautious optimism within the scientific and medical communities.
Turning Cancer’s Protective Systems into Fatal Flaws
The scientific ingenuity behind this new therapeutic strategy lies in its counter-intuitive logic. Mesothelioma cells, much like many other cancer cells, exhibit heightened metabolic activity, a characteristic that fuels their rapid proliferation. A byproduct of this accelerated metabolism is the unusually high production of "reactive oxygen species" (ROS) – unstable molecules that can inflict severe damage on cellular components. To counteract this inherent oxidative stress, cancer cells develop robust defense mechanisms, significantly increasing their production of antioxidant enzymes. These enzymes act as cellular guardians, neutralizing the damaging ROS and enabling the tumor to thrive in an otherwise hostile environment.
One such crucial antioxidant enzyme is peroxiredoxin 3, or PRX3, which operates within the mitochondria – the vital powerhouses responsible for generating most of a cell’s energy. Traditionally, cancer research has explored the therapeutic potential of boosting antioxidants to combat cancer by reducing ROS levels. However, many clinical trials based on this premise have failed, with some studies even suggesting that excessive antioxidant supplementation could inadvertently support tumor growth by alleviating cellular stress.
The UVM researchers, however, decided to invert this conventional wisdom. Instead of augmenting antioxidant defenses, they posed a radical question: what if cancer cells were deprived of one of their most critical antioxidant shields? Their innovative approach focuses on specifically blocking PRX3. The premise is elegant: without this essential protective enzyme, oxidative stress within tumor cells would accumulate unchecked, eventually overwhelming their capacity to cope and leading to programmed cell death.
Thiostrepton: An Antibiotic Repurposed to Overload Tumor Cells
The experimental treatment, developed by RS Oncology, builds directly upon the foundational discoveries made at UVM. The drug utilizes thiostrepton, a naturally occurring antibiotic, to precisely disable PRX3. The mechanism of action is compelling: by blocking PRX3, thiostrepton causes hydrogen peroxide – a potent ROS – to accumulate within the mitochondria of tumor cells. This toxic buildup ultimately triggers a cascade of events leading to mitochondrial dysfunction and, critically, cell death.
Cancer cells appear to be uniquely vulnerable to this strategy for several reasons. Their already elevated baseline production of reactive oxygen species means they are operating closer to a critical threshold of oxidative stress. Furthermore, PRX3 exhibits a more rapid turnover rate in tumor cells compared to healthy cells. This differential activity potentially allows the treatment to selectively target cancerous tissues, minimizing adverse effects on healthy, normal cells.
Laboratory experiments provided compelling evidence supporting the central role of PRX3 in mesothelioma survival. When researchers genetically deleted PRX3 from mesothelioma tumor cell lines, the consequences were dramatic: mitochondrial function significantly declined, cell growth was sharply inhibited, and, crucially, the cancer cells lost their ability to form tumors in animal models. This preclinical data strongly validated the therapeutic potential of PRX3 inhibition.
A key concern in targeting mitochondria, given their indispensable role in nearly every cell, has traditionally been the potential for widespread toxicity. However, other independent research groups have demonstrated that genetically eliminating PRX3 in healthy mice does not produce adverse effects, and the animals develop and function normally. This finding is profoundly important. "People will come up to us at conferences and state that you can’t target the mitochondria because they’re too important," remarks Victoria Gibson. "The evidence – that you can knock out PRX3 in mice and there’s no adverse phenotype – supports our approach." This robust preclinical safety profile bolstered confidence in advancing the strategy to human trials.
From UVM Laboratory to Human Patients: A Chronology of Discovery
The journey from a promising laboratory observation to a potential clinical treatment is long and complex, marked by rigorous scientific inquiry and strategic partnerships. The scientific groundwork for this novel treatment commenced at UVM’s Cancer Center around 2015. Early experiments with thiostrepton yielded encouraging results, laying the foundation for what would become a significant breakthrough.
Recognizing the immense translational potential of these UVM discoveries, researchers, including Brian Cunniff, co-founded RS Oncology, a private pharmaceutical company specifically established to shepherd these academic insights through the demanding stages of clinical development. Professor Cunniff, an associate professor in the Department of Pathology and Laboratory Medicine at UVM’s Larner College of Medicine, also serves as the company’s chief science officer, ensuring continuity between scientific discovery and clinical application.
The team meticulously transformed thiostrepton into a refined clinical formulation designated RSO-021. This crucial step involved extensive pharmaceutical development to ensure the drug’s stability, bioavailability, and suitability for human administration.
Between 2022 and 2023, RSO-021 underwent its pivotal phase one clinical trial in the United Kingdom. This study was conducted under the stringent oversight of the Medicines and Healthcare products Regulatory Agency (MHRA), the UK’s equivalent of the U.S. Food and Drug Administration (FDA). The choice of local delivery was strategic: the treatment is administered directly into the chest cavity via a catheter, a device many mesothelioma patients already have in place to manage "pleural effusions"—a common and debilitating buildup of fluid in the space between the lung and chest wall. Approximately 90 percent of mesothelioma patients develop these effusions. This localized delivery method allows for a high concentration of the drug to be delivered directly to the tumor site, minimizing systemic exposure and potential side effects throughout the rest of the body.
Encouraging Early Clinical Trial Results and Broader Implications
The phase one study successfully met its primary endpoints of safety and tolerability at a dose of 90 milligrams. Crucially, no patient deaths were attributed to the experimental drug, a paramount consideration in early-stage trials involving critically ill individuals. Furthermore, researchers obtained biopsy samples from patients and found compelling evidence that RSO-021 was indeed engaging its intended biological target—PRX3—within human tumor tissue. This confirmed that the molecular mechanism observed in preclinical laboratory models and animal experiments was faithfully replicated in human patients, a vital validation of the drug’s mechanism of action.
In terms of efficacy, the average progression-free survival (PFS) in the trial was 4.2 months, a figure roughly comparable to existing treatments for mesothelioma. However, the researchers were particularly encouraged by the overall survival (OS) data. Among the 15 patients in the cohort, survival outcomes surpassed what is typically observed with currently available therapies for this aggressive disease. Professor Cunniff described this finding as a potential "game changer," highlighting its significance. "Our overall survival data is very promising and will hopefully persist with additional patients," Cunniff stated, underscoring the need for further validation in larger trials.
Intriguingly, the findings also suggest that RSO-021 may exert effects beyond direct cancer cell killing. There is preliminary evidence that the drug may also modulate the immune environment surrounding the tumor, potentially enhancing the immune system’s ability to recognize, 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," Cunniff explained, pointing to a dual mechanism that could amplify its therapeutic impact.
Following the successful completion of Phase 1, the phase two clinical trial has now concluded. The research team is eagerly preparing to present these results at a major global oncology meeting later this year, a presentation that is highly anticipated by the cancer research community.
Expanding the Strategy Beyond Mesothelioma
The promising results from the RSO-021 program are propelling the research in multiple new directions. Scientists from UVM and RS Oncology, in collaboration with the University of Leicester and other institutions in the UK, are actively developing second-generation PRX3 inhibitors. A key focus of this next phase of development is to improve the solubility of these compounds. Enhanced solubility could pave the way for future versions of the drug to be formulated as oral tablets, which would significantly simplify administration and potentially broaden its applicability beyond mesothelioma to a wider range of cancers.
At UVM, Victoria Gibson, the lead author of the recent Nature Communications study, continues to drive this innovative research forward as a postdoctoral researcher. Her current work involves launching investigations into the potential of thiostrepton for treating peritoneal malignancies, a group that includes peritoneal mesothelioma, gastric cancer, and other gastrointestinal cancers. This expansion is being conducted in collaboration with Conor O’Neill, a surgical oncologist at the UVM Cancer Center and UVM Health, underscoring the multidisciplinary nature of modern cancer research. "We believe this mechanism could be applicable to other cancers," Cunniff affirmed, highlighting the broad therapeutic potential of PRX3 inhibition.
The Human Element: Driving Scientific Progress
For researchers like Victoria Gibson, witnessing the progression of her work from abstract laboratory experiments to tangible human clinical trials has instilled a profound and deeply personal dimension to the project. "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 shared, articulating the universal motivation that often drives cancer scientists.
Despite her dedicated pursuit of scientific discovery, Gibson admitted to being taken aback when a family member contacted the laboratory, expressing a desperate hope to enroll her dying father in the clinical trial. This moment served as a powerful reminder of the real-world impact of her work. "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." This poignant connection between rigorous scientific endeavor and the urgent needs of patients underscores the critical importance of translational research and offers a glimmer of hope in the fight against some of the most challenging cancers. The scientific community eagerly awaits the full results of the Phase 2 trial, hopeful that RSO-021 will continue to demonstrate its potential to transform the lives of patients facing mesothelioma and beyond.
