Cancer Drug Offers New Hope for Mesothelioma Patients
Mesothelioma, a rare and aggressive cancer primarily caused by asbestos exposure, has long been a challenging disease to treat. With a median survival of just 12 months and a five-year survival rate of around 10%, it's a devastating diagnosis for patients and their families. But a recent study published in Nature Communications offers a glimmer of hope, presenting a novel approach to treating this devastating disease.
The research, led by Professor Brian Cunniff and Victoria Gibson from the University of Vermont (UVM), along with an international team of collaborators, focuses on a counterintuitive strategy: turning cancer's own defenses against it. By inhibiting a specific enzyme called peroxiredoxin 3 (PRX3), the team aims to overwhelm tumor cells with oxidative stress, ultimately leading to their death.
The study, funded by RS Oncology, LLC, involved a phase one clinical trial in which patients with relapsed mesothelioma were given the new drug. The results were remarkable: 67% of patients experienced controlled disease progression, and some tumors even shrank. Crucially, the drug was well-tolerated, and patients lived longer than those receiving standard treatments.
The key to this approach lies in the unique properties of tumor cells. Tumors generate elevated levels of reactive oxygen species, which can be harmful. To counteract this, tumor cells produce antioxidant enzymes like PRX3, which protect them from oxidative stress. The UVM team's insight was to flip this conventional logic.
Instead of increasing antioxidants, they decided to inhibit PRX3, causing a buildup of hydrogen peroxide in the mitochondria of tumor cells. This triggers the cells' death, as they are unable to cope with the increased oxidative stress. The fact that tumor cells generate more reactive oxygen species than normal cells means that PRX3 turns over faster in tumors, making the treatment more selective for cancer cells.
The team's research also addressed a common concern about targeting mitochondria. By deleting PRX3 in mesothelioma tumor cell lines and healthy mice, they found no adverse effects. This demonstrates the safety and potential of their approach.
The laboratory foundation for this work was established at UVM's Cancer Center around 2015. Seeing promising early results with thiostrepton, a naturally occurring antibiotic used to disable PRX3, a team formed RS Oncology to translate UVM findings into the clinic. Brian Cunniff, an associate professor at UVM, serves as the company's chief science officer.
The drug is administered directly into the chest through a catheter already in place for patients with pleural effusions, a common issue in mesothelioma patients. This local delivery ensures the drug concentrates at the tumor site while minimizing systemic exposure.
The phase one trial met its safety and tolerability requirements, with no patient deaths attributed to the drug. Crucially, the team demonstrated on-target engagement in patient tissue samples, confirming the drug's mechanism of action works in human tumors.
The results were promising: progression-free survival averaged 4.2 months, comparable to current therapies. More significantly, overall survival in the cohort of 15 patients was better than existing treatments, a finding Cunniff describes as a potential 'game changer'.
The team's data also suggests the new drug may help awaken the immune system to attack or slow the tumor. This dual cytotoxic and immunomodulatory activity is a significant advantage.
Phase two of the drug trial has been completed, and results are expected to be presented at a global oncology meeting this year. The research program is expanding, with the UVM and RS Oncology team developing second-generation PRX3 inhibitors that are more soluble and potentially deliverable as an oral tablet.
For Victoria Gibson, the lead author on the study, the work is deeply personal. Her desire to help people, driven by her own experiences with cancer, is a powerful motivation. The fact that a family member wanted to enroll her dying father in the clinical trial was a profound moment for her.
As the research continues to advance, the potential for a breakthrough in mesothelioma treatment becomes increasingly tangible. The development of a more easily deliverable oral formulation and the exploration of its application to other cancer types could revolutionize cancer care, offering new hope to patients worldwide.
