Recent Cancer Research Advances Span Treatments and Biomarkers

Patients with relapsed mesothelioma who received an experimental drug called RSO-021 in a phase one clinical trial experienced disease control in 67% of cases, with some patients also showing tumor shrinkage. The treatment was generally well tolerated, and these critically ill patients survived longer than patients receiving standard therapies, according to a study published in Nature Communications by researchers at the University of Vermont.

Mesothelioma is rare but highly aggressive, affecting about 30,000 people worldwide each year. Immunotherapy and chemotherapy provide only limited benefits, and patients typically survive about 12 months after diagnosis, with only around 10 percent alive five years later. Mesothelioma cells produce unusually high amounts of reactive oxygen species and increase production of the antioxidant enzyme peroxiredoxin 3 (PRX3), which shields tumor cells from damaging molecules created by their accelerated metabolism. The experimental drug RSO-021, developed by RS Oncology from the naturally occurring antibiotic thiostrepton, disables PRX3, causing hydrogen peroxide to accumulate within tumor cell mitochondria and triggering cell death. Because cancer cells generate more reactive oxygen species than healthy cells, the drug may affect tumor cells more selectively while reducing damage to normal tissue.

In laboratory experiments, completely removing PRX3 from mesothelioma cell lines reduced mitochondrial activity and slowed cell division sharply, and the altered cancer cells failed to produce tumors in animal experiments. Research from other groups has shown that healthy mice lacking PRX3 did not develop harmful effects. Between 2022 and 2023, researchers tested RSO-021 in a phase one trial conducted in the United Kingdom under the supervision of the MHRA. The medication is delivered directly into the chest through a catheter already used by patients with pleural effusions, a complication affecting approximately 90 percent of people with mesothelioma. At a dose of 90 milligrams, the trial met its goals for safety and tolerability, with no deaths attributed to the treatment.

In a separate development, a research team from Huntsman Cancer Institute at the University of Utah reported that the investigative compound daraxonrasib could be an effective treatment for NRAS-driven melanoma, an aggressive type of skin cancer driven by mutations in the NRAS gene, which is mutated in roughly a quarter of melanoma cases. Daraxonrasib, developed by Revolution Medicines, targets and inhibits RAS, a protein that drives cancer when altered. The results of daraxonrasib as a treatment for metastatic pancreatic cancer, in which it doubled patients' life expectancy in a Phase 3 clinical trial, recently received a standing ovation from physicians at the American Society of Clinical Oncology Annual Meeting. In the melanoma study, published in Cancer Research, all NRAS-driven models were very responsive to the RAS inhibitor. The team noted that shrinkage of NRAS-driven tumors is actually quite rare. Patients with NRAS-driven melanoma do not have effective targeted therapies as a secondary line of treatment after immunotherapy, which is effective in about half of melanoma patients. The team observed that some models became resistant to the drug, with resistance tied to mutations in MEK1 or loss of expression of cyclophilin A.

Researchers at the University of Birmingham identified a new biomarker for response to a specific cancer therapy in children with Ewing Sarcoma and other tumor types. The study, a Phase I/II treatment arm within the eSMART Trial, recruited 70 patients, of whom 66 were treated across the UK, France, the Netherlands and Spain. Of these, 36 had Ewing Sarcoma and 34 had various other tumor types. The chances of a cure significantly decrease to less than 30% if the cancer has spread or recurs. The combination of low-dose irinotecan, a chemotherapy drug, and a PARP inhibitor was tolerated and effective, with 12 patients benefiting across the different tumor types, either responding with partial or complete tumor shrinkage or showing stable disease for more than six months. Retrospective analysis revealed that patients whose cancers had a high aneuploidy score were significantly more likely to benefit from therapy. This is the first time that aneuploidy score has been associated with response to therapy in a pediatric cancer trial.

Researchers at the Federal University of São Paulo (UNIFESP) in Brazil identified a molecule on the surface of cells, the Sindecam-4 (SDC4) receptor, as a promising therapeutic target against cancer. The study, published in Cytotechnology, showed that overexpression of SDC4 provides tumor cells with a protective shield. In laboratory experiments, silencing the receptor halted the accelerated growth of tumor cells, causing them to resume responding to programmed cell death. SDC4 protects tumor cells from anoikis, a form of cell death caused by loss of adhesion to their substrate. In experiments on adherent aortic endothelial cells from rabbits, fewer than 5% survived disruption of adhesion and became highly aggressive with SDC4 overexpression; when the molecule was silenced, the cells lost their malignant properties and became dependent on adhesion once again. The mechanism involves modulation of the cell cycle, with silencing increasing an inhibitor of cell division called p27 and regulating the expression of cyclin and CDK. The researchers are now investigating whether cannabidiol (CBD) can act on SDC4 molecules.

University of Birmingham researchers are investigating ways to improve treatment pathways for patients with cholangiocarcinoma, a rare bile duct cancer with a survival rate of around 5%. The research, supported by a philanthropic donation from Darren and Katie Nelson, focuses on a recent clinical trial that identified promising results using the immune-boosting drug durvalumab, which turbo-charges cancer-fighting T cells. The team wants to find out more about how T cells treated with durvalumab might interact with cancer cells in the bile duct, and initial experiments have used genomics expertise to identify changes in T cells that might indicate whether the therapy is working and whether patients are at risk of side effects. An additional goal is reducing the time taken between diagnosis and treatment.