Mesothelioma, a rare and aggressive cancer primarily caused by asbestos exposure, has long been a challenging disease to treat. Current treatments, such as immunotherapy and chemotherapy, offer limited benefits, with patients facing a grim prognosis. However, a recent study published in Nature Communications has brought a glimmer of hope to those affected by this devastating disease.
The study, led by Professor Brian Cunniff and Victoria Gibson from the University of Vermont (UVM), introduces a novel approach to treating mesothelioma and potentially other cancers. By targeting a specific enzyme called peroxiredoxin 3 (PRX3), the research team has developed a drug that shows remarkable promise in controlling disease progression and even shrinking tumors.
The key insight behind this approach is to flip the conventional logic of cancer treatment. Instead of increasing antioxidants to combat the elevated levels of reactive oxygen species (ROS) produced by tumor cells, the UVM team decided to inhibit PRX3. This enzyme, which is crucial for tumor cells to survive oxidative stress, was the target of their innovative drug.
The drug, developed by RS Oncology, LLC, utilizes thiostrepton, a naturally occurring antibiotic, to disable PRX3. This inhibition leads to a buildup of hydrogen peroxide in the mitochondria of tumor cells, ultimately triggering their death. The study's findings are particularly striking, as the drug controlled disease progression in 67% of patients and even caused tumors to shrink in some cases.
What makes this approach even more remarkable is the drug's well-tolerated nature. Despite the critically ill patients' condition, the drug was administered safely, and patients lived longer than those receiving standard treatments. This is a significant achievement, as it demonstrates the potential for a more effective and tolerable treatment option for mesothelioma patients.
The UVM team's research also addresses a common concern about targeting mitochondria. By deleting PRX3 in mesothelioma tumor cell lines and healthy mice, they showed that the enzyme's removal had no adverse effects on the animals' overall health. This finding supports the safety and feasibility of targeting mitochondria for cancer treatment.
The journey from the laboratory to the clinic has been a collaborative effort. The initial research was conducted at UVM's Cancer Center, and the promising results led to the formation of RS Oncology, a private pharmaceutical company. Brian Cunniff, an associate professor at UVM, serves as the company's chief science officer, overseeing the translation of the UVM findings into a novel clinical formulation called RSO-021.
The phase one clinical trial, conducted in the United Kingdom, demonstrated the drug's safety and tolerability at a 90-milligram dose. Crucially, the team confirmed that the drug's mechanism of action works in human tumors, mirroring the observations made in cells and mice in the laboratory.
The trial's results are impressive, with a progression-free survival average of 4.2 months, comparable to current therapies. However, the most significant finding is the overall survival improvement in the cohort of 15 patients, which Cunniff describes as a potential 'game changer'.
The study also suggests that the new drug may have immunomodulatory effects, helping to awaken the immune system to attack or slow the tumor. This dual cytotoxic and immunomodulatory activity is a promising feature that could enhance the drug's effectiveness.
Looking ahead, the research program is expanding in multiple directions. The UVM and RS Oncology team, in collaboration with the University of Leicester and other institutions, is developing second-generation PRX3 inhibitors that are more soluble and potentially deliverable as an oral tablet. This could broaden the drug's application beyond mesothelioma and make it more accessible.
For Victoria Gibson, the lead author on the study, the personal connection to the research is profound. Her desire to help people affected by cancer, whether through personal experience or those around her, drives her passion for this work. The unexpected call from a family member seeking to enroll her dying father in the clinical trial highlighted the profound impact of their research.
As the study progresses, the potential for a breakthrough treatment for mesothelioma and other cancers becomes increasingly evident. The innovative approach of targeting PRX3 and the promising results from the clinical trial make this research a beacon of hope for patients and a testament to the power of scientific discovery.
