In the world of cancer research, where hope often meets despair, a recent study has emerged as a beacon of promise for patients suffering from mesothelioma, a rare and aggressive cancer with a grim prognosis. This study, led by Professor Brian Cunniff and his team at the University of Vermont (UVM), introduces a novel approach to treating mesothelioma that challenges conventional wisdom and offers a glimmer of light in the darkness. What makes this discovery particularly exciting is its potential to not only extend survival but also to revolutionize our understanding of cancer treatment.
A Disease of Unmet Need
Mesothelioma, a cancer primarily caused by asbestos exposure, has long been a formidable foe. With a median survival of around 12 months and a five-year survival rate of just 10%, it presents a significant unmet medical need. The current treatments, immunotherapy and chemotherapy, offer limited benefit, leaving patients and their families desperate for new options. This is where the UVM team's research comes in, offering a fresh perspective on a disease that has long been considered incurable.
Turning Cancer's Defenses Against Itself
The key to this breakthrough lies in understanding the unique biology of mesothelioma tumors. Like many cancers, mesothelioma cells generate high levels of reactive oxygen species (ROS), which are unstable and damaging molecules that can lead to cell damage and death. To survive under these conditions, tumor cells produce antioxidant enzymes, such as peroxiredoxin 3 (PRX3), which protect them from oxidative stress. The UVM team's insight was to flip this conventional logic on its head.
Instead of trying to increase antioxidants to combat cancer, as previous clinical trials had done, the team decided to inhibit PRX3, overwhelming tumor cells with oxidative stress and ultimately killing them. This counterintuitive approach is what sets their research apart and has led to some remarkable results.
From Laboratory to Clinic
The laboratory foundation for this work was established at UVM's Cancer Center around 2015. Seeing promising early results with thiostrepton, an antibiotic that can disable PRX3, the team formed RS Oncology, a private pharmaceutical company, to translate their findings into the clinic. UVM's Brian Cunniff, an associate professor in the Department of Pathology and Laboratory Medicine, serves as the company's chief science officer.
The clinical trial, conducted in the United Kingdom under the oversight of the MHRA, administered the drug directly into the chest through a catheter already in place for patients with pleural effusions, a buildup of fluid between the lung and chest wall that affects approximately 90% of mesothelioma patients. This local delivery concentrated the drug at the tumor site while limiting systemic exposure.
Results and Implications
The phase one trial 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 in the laboratory, 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'.
What makes this discovery even more exciting is the potential for immunomodulatory activity. The drug not only has cytotoxic activity, killing tumor cells, but it also modulates the immune system to manage the tumor. This dual action could be a significant advancement in cancer treatment, offering a more comprehensive approach to tackling this complex disease.
Looking Ahead
The research program is expanding on multiple fronts. The UVM and RS Oncology team, in collaboration with the University of Leicester and other institutions in the UK, are developing second-generation PRX3 inhibitors that are more soluble and potentially deliverable as an oral tablet. This could allow the drug to be brought to market more easily and have application with cancer types beyond mesothelioma.
At UVM, Victoria Gibson, the lead author on the new study, is remaining as a postdoctoral researcher to help initiate new research using thiostrepton for peritoneal malignancies, including mesothelioma, gastric cancer, and other gastrointestinal cancers, in collaboration with Conor O'Neill, a surgical oncologist at the UVM Cancer Center and UVM Health. Gibson's personal connection to the work, stemming from a family member's desire to enroll in the clinical trial, adds a layer of emotion and motivation to the research.
In conclusion, this study represents a significant step forward in the fight against mesothelioma and offers a glimmer of hope for patients and their families. The potential for this drug to extend survival and revolutionize our understanding of cancer treatment is immense. As the research program expands and the results of the phase two trial are expected, the future looks bright for those affected by this devastating disease.
