A potential target for experimental drugs that block PRMT5 — a naturally occurring enzyme some tumors rely more on for survival — has been identified by researchers with the Fralin Biomedical Research Institute's Cancer Research Center in Washington, D.C.
In a study published this month in Cancer Research , Assistant Professor Kathleen Mulvaney of Virginia Tech's Fralin Biomedical Research Institute shared research that could help guide development of new therapies for some treatment-resistant lung, brain, and pancreatic cancers.
"Using genetic screening, we found a new drug combination that seemingly works," Mulvaney said.
New therapies are needed. Lung cancer is a leading cause of cancer-related death globally. The five-year survival rate is less than 15 percent for pancreatic cancer patients, and even lower for glioblastoma.
"With one drug alone, tumors can become resistant really quickly," said Mulvaney, who is a member of the research institute's Cancer Research Center in Washington, D.C. Treatment often fails. The findings suggest the PRMT5 inhibitor could be a powerful new approach for certain hard-to-treat cancers. "In all cases, the combination is better at killing than the single agents."
Many of these solid tumors share a genetic trait: They lack CDKN2A and MTAP, two genes that suppress tumors and help regulate cell growth. Without them, the cancers become dependent on PRMT5 and potentially vulnerable to drugs that block the enzyme.
Mulvaney and colleagues analyzed genetic data from thousands of cancer patients available through the cBioPortal.
They applied CRISPR editing tools to look at biological pathways across a range of samples to determine which genes make cancer cells more vulnerable to PRMT5 inhibitors and which combinations could improve response and long-term outcomes.
An estimated 5 percent of all cancer patients — about 80,000 to 100,000 per year in the U.S. — can benefit from the therapies identified, according to Mulvaney, who also holds an appointment in biomedical sciences and pathobiology in the Virginia-Maryland College of Veterinary Medicine.
Using PRMT5 inhibitors with drugs that block a communication system that tells cancer cells when to grow, divide, or shut down — known as the MAP kinase pathway — scientists identified potential treatments for clinical trials.
"We also discovered a number of genes that interact with PRMT5 signaling in cancer that were not previously known," Mulvaney said.
In addition to lung, brain, and pancreatic cancers, the treatment shows promise for some types of melanoma and mesothelioma.
In both animal models and cell cultures derived from patient tissue, lab members saw success after testing potential therapies.
"In all cases, the combination is better at killing cancer cells than the single agents," Mulvaney said. "Only the combinations led to complete regressions."
The research was supported by a postdoctoral training fellowship and investigators' research award from the National Institutes of Health (NIH), as well as grant funding from the NIH's National Cancer Institute (NCI). The study also received support and funding awards from: the Broad Institute; the V Foundation; the Claudia Adams Barr Program and Hale Family Center for Pancreatic Cancer Research, both of the Dana-Farber Cancer Institute; and DAAD Promos and Marshall Plan scholarships.
DOI: 10.1158/0008-5472.CAN-25-1464
