By Budi Oetomo Narendra 
This devastating diagnosis, affecting approximately 30,000 individuals globally each year, has historically presented a formidable challenge to the medical community, characterized by limited treatment options and a grim prognosis. However, groundbreaking research emerging from the University of Vermont (UVM) and published in Nature Communications offers a beacon of hope, describing an innovative strategy that not only controls disease progression but also shows promising signs of extending survival in critically ill patients. This novel approach, which involves turning cancer’s own protective mechanisms against itself, could revolutionize the treatment landscape for mesothelioma and potentially other malignancies.
The Enduring Challenge of Mesothelioma
Mesothelioma is a malignancy of the mesothelium, the protective lining that covers many internal organs, most commonly the pleura (lining of the lungs) but also the peritoneum (lining of the abdomen) and, rarely, the pericardium (lining of the heart) or tunica vaginalis (lining of the testis). Its strong association with asbestos exposure, a ubiquitous material used extensively in construction, shipbuilding, and manufacturing throughout the 20th century, makes it a largely preventable, yet persistent, public health crisis. The latency period between initial asbestos exposure and the manifestation of mesothelioma can span 20 to 50 years, meaning that individuals exposed decades ago are still at risk.
The global incidence of mesothelioma reflects this historical exposure, with countries like the UK, Australia, and the Netherlands, which historically had high rates of asbestos use, continuing to report significant numbers of new cases. Despite bans on asbestos in over 60 countries, many nations still permit its use, and the legacy of past exposure ensures that mesothelioma will remain a clinical concern for decades to come.
Current treatment options for mesothelioma are notoriously limited and often provide only marginal benefits. Standard approaches typically involve a combination of chemotherapy (often platinum-based drugs like cisplatin or carboplatin combined with pemetrexed), radiation therapy, and, in select cases, aggressive surgery. More recently, immunotherapy, utilizing checkpoint inhibitors such as nivolumab and ipilimumab, or pembrolizumab, has shown efficacy in some patients, offering a new avenue for treatment. However, despite these advancements, the disease remains exceptionally difficult to control, with patients facing a median survival of approximately 12 months and a five-year survival rate hovering around a mere 10 percent. The vast majority of patients are men, often with a history of occupational exposure in industries like shipbuilding, oil refining, and asbestos manufacturing. This dire outlook underscores the urgent and significant unmet medical need, as articulated by Brian Cunniff, a professor at the University of Vermont and a key figure in the new research.
A Novel Therapeutic Strategy: Exploiting Cancer’s Vulnerabilities
The UVM research team, led by Professor Cunniff and research scientist Victoria Gibson, in collaboration with an international network of scientists, has unveiled an unconventional strategy that challenges long-held assumptions in cancer therapy. Their approach zeroes in on a fundamental characteristic of cancer cells: their highly active metabolisms, which generate unusually high levels of "reactive oxygen species" (ROS). These unstable molecules, while naturally occurring, can cause significant damage to cells, driving oxidative stress.
To survive this inherently stressful environment, cancer cells have evolved sophisticated defense mechanisms, including an increased production of antioxidant enzymes that neutralize these damaging ROS molecules. One such crucial enzyme is peroxiredoxin 3, or PRX3, which operates within the mitochondria – the cellular powerhouses responsible for generating most of a cell’s energy.
Historically, cancer research explored the idea of boosting antioxidants to combat cancer by reducing ROS. However, many clinical trials based on this premise failed, and some studies even suggested that enhancing antioxidant levels could inadvertently aid tumor growth by protecting cancer cells from their own destructive internal environment. The UVM team ingeniously reversed this logic, asking a pivotal question: what if cancer cells were deprived of one of their most vital antioxidant defenses?
Their innovative strategy centers on blocking PRX3. By disabling this protective enzyme, oxidative stress is allowed to build unchecked within tumor cells. The accumulation of hydrogen peroxide, a potent reactive oxygen species, inside the mitochondria eventually reaches catastrophic levels, triggering programmed cell death. This targeted disruption effectively turns cancer’s protective system into a fatal weakness.
The Journey of RSO-021: From UVM Lab to Human Trials
The genesis of this experimental treatment, now known as RSO-021, traces back to foundational discoveries made at UVM’s Cancer Center around 2015. Early laboratory experiments with thiostrepton, a naturally occurring antibiotic, demonstrated its remarkable ability to disable PRX3. Recognizing the immense potential of these findings, researchers helped establish RS Oncology, LLC, a private pharmaceutical company specifically created to translate these UVM discoveries into clinical applications. Brian Cunniff, who is also an associate professor in the Department of Pathology and Laboratory Medicine at UVM’s Larner College of Medicine, serves as the company’s chief science officer, bridging the gap between academic research and pharmaceutical development.
The team meticulously refined thiostrepton into a clinically viable formulation, RSO-021, designed for optimal delivery and efficacy. This rigorous preclinical development paved the way for human trials. Between 2022 and 2023, RSO-021 entered a Phase 1 clinical trial conducted in the United Kingdom under the stringent oversight of the Medicines and Healthcare products Regulatory Agency (MHRA), the UK’s equivalent of the U.S. FDA.
A significant advantage of RSO-021’s administration method is its local delivery directly into the chest cavity. This is facilitated by a catheter that 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, affecting approximately 90 percent of mesothelioma patients. This localized delivery approach allows for a high concentration of the drug directly at the tumor site, maximizing its therapeutic effect while simultaneously minimizing systemic exposure and potential side effects throughout the rest of the body.
Encouraging Phase One Results and Mechanism Confirmation
The Phase 1 clinical trial successfully met its primary objectives of assessing safety and tolerability at a dose of 90 milligrams. Crucially, no patient deaths were attributed to the experimental drug, a paramount consideration in early-phase oncology trials involving critically ill individuals.
Beyond safety, researchers found compelling evidence within patient tissue samples that RSO-021 was effectively engaging its intended biological target, PRX3. This crucial finding confirmed that the mechanism of action observed in preclinical laboratory experiments with cells and animal models was indeed operational in human tumors, providing robust validation for the therapeutic strategy.
While the average progression-free survival (PFS) of 4.2 months was comparable to existing treatments, the researchers were particularly encouraged by the overall survival (OS) data. Among the 15 patients in the cohort, survival outcomes were demonstrably better than what is typically observed with currently available standard therapies for relapsed mesothelioma. Professor Cunniff cautiously but optimistically described this finding as a potential "game changer," emphasizing the critical need for further validation in larger cohorts. "Our overall survival data is very promising and will hopefully persist with additional patients," he stated.
Furthermore, the study yielded intriguing insights suggesting that RSO-021 may exert its therapeutic effects through a dual mechanism. In addition to directly inducing cytotoxic activity and killing cancer cells, the drug appears to alter the immune microenvironment surrounding the tumor. This immunomodulatory capacity could potentially enhance the body’s own immune system to better attack or restrain the cancer, a synergistic effect that could significantly improve long-term outcomes. "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.
The successful completion of Phase 2 of the clinical trial has now been announced, and the researchers anticipate presenting these comprehensive results at a major global oncology meeting later this year, a pivotal step towards potential regulatory approval.
The Scientific Rationale: Why Cancer Cells Are Vulnerable
The selective vulnerability of cancer cells to PRX3 inhibition stems from several key biological differences compared to healthy cells. Cancer cells, due to their rapid proliferation and altered metabolism, already operate under a higher baseline level of oxidative stress, producing more reactive oxygen species than normal cells. This inherent stress makes them exquisitely dependent on their antioxidant defenses, including PRX3. Depriving them of this critical enzyme pushes them beyond a compensatory threshold, leading to an irreversible accumulation of damage and subsequent cell death.
Moreover, PRX3 is observed to turn over more rapidly in tumor cells, a characteristic that could allow RSO-021 to selectively target cancer cells while having a less pronounced effect on healthy tissue, which maintains a more balanced redox state and less reliance on hyperactive PRX3.
Robust laboratory experiments provided further substantiation for PRX3’s indispensable role in mesothelioma survival. When researchers genetically deleted PRX3 from mesothelioma tumor cell lines, they observed a significant decline in mitochondrial function, a sharp deceleration in cell growth, and, critically, the inability of these cancer cells to form tumors in animal models. These preclinical findings strongly supported the hypothesis that PRX3 is a critical dependency for mesothelioma proliferation and survival.
A key concern in targeting mitochondria, given their essential functions in nearly every cell type, has been potential systemic toxicity. However, research from other groups has demonstrated that eliminating PRX3 in healthy mice does not produce adverse effects. This crucial finding allays concerns about broad mitochondrial toxicity, strongly supporting the safety and specificity of the UVM team’s approach. "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 essence, mice lacking the genes responsible for producing PRX3 can develop and function normally, providing a strong biological rationale for the therapeutic window of PRX3 inhibition.
Expanding Horizons: Beyond Mesothelioma
The promising results in mesothelioma have catalyzed the expansion of this research into several new directions. Scientists from UVM and RS Oncology, in collaboration with institutions like the University of Leicester and other UK partners, are actively developing second-generation PRX3 inhibitors. These next-generation compounds aim to improve properties such as solubility, potentially enabling future versions to be administered as an oral tablet. An oral formulation would significantly enhance ease of administration and could broaden the treatment’s applicability beyond localized delivery for mesothelioma, making it accessible for a wider range of patients and cancer types.
At UVM, Victoria Gibson, the lead author of the recent Nature Communications study, is continuing her pioneering work as a postdoctoral researcher. She is spearheading investigations into the potential of thiostrepton in peritoneal malignancies, including peritoneal mesothelioma, gastric cancer, and other gastrointestinal cancers. This collaborative effort with Conor O’Neill, a surgical oncologist at the UVM Cancer Center and UVM Health, underscores the belief that this fundamental mechanism of targeting PRX3 could be applicable to a broader spectrum of cancers that share similar metabolic vulnerabilities. "We believe this mechanism could be applicable to other cancers," Cunniff affirmed.
For the researchers involved, particularly Gibson, witnessing their laboratory discoveries translate into tangible hope for human patients has imbued the project with a profound personal dimension. "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 reflected. This personal connection was profoundly amplified when a family member contacted the laboratory, desperately hoping to enroll her dying father in the clinical trial. "We just work in a lab all day working with cells," Gibson 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."
The journey from a basic science discovery at a university lab to an experimental drug showing promise in human trials is long, arduous, and fraught with challenges. The success of RSO-021 in its early clinical phases represents a monumental step forward, not just for mesothelioma patients, but for the broader field of oncology, demonstrating the power of innovative thinking in exploiting fundamental cancer biology to develop effective, targeted therapies. As the results of Phase 2 are anticipated and further research unfolds, the prospect of a new treatment paradigm for devastating cancers moves closer to reality, offering a much-needed glimmer of hope where historically there has been little.
