Hard-to-Treat Cancers Respond to New Therapy

A promising new combination therapy is offering new hope for patients with hard-to-treat cancers.

This is thanks to scientists at the Fralin Biomedical Research Institute in Virginia who have identified a potential target for experimental drugs that block PRMT5—a naturally occurring enzyme some tumors rely more on for survival.

The study could help guide the development of new therapies for some treatment-resistant lung, brain and pancreatic cancers, according to the researchers.

“Using genetic screening, we found a new drug combination that seemingly works,” said paper author and cancer biologist professor Kathleen Mulvaney in a statement.

Lung cancer is by far the most fatal type of cancer in the US, accounting for about one in five of all cancer deaths. Meanwhile, the five-year survival rate is less than 15 percent for pancreatic cancer patients (although this can vary depending on the stage of cancer) and even lower for glioblastoma, a fast growing type of brain tumor. While treatment options are available, the need for new types is also clear.

“With one drug alone, tumors can become resistant really quickly,” Mulvaney said. “In all cases, the combination is better at killing than the single agents.”

The findings suggest the PRMT5 inhibitor could be a powerful new approach for these hard-to-treat cancers. Many of these types of solid tumors share a genetic trait—they lack the genes CDKN2A and MTAP. Both of these are important as they suppress tumors and help to regulate cell growth.

Without them, the cancers become dependent on PRMT5 and potentially vulnerable to drugs that lock the enzyme.

“It’s very difficult to make a drug against the absence of something, so the discovery that PRMT5 is a target we can make a drug against is very exciting to treat CDKN2A/MTAP deleted cancers,” Mulvaney told Newsweek.

“A new revolutionary class of inhibitors, referred to as MTA-cooperative PRMT5 inhibitors, has shown promising results in ongoing early phase clinical trials,” the researchers also explained in the paper.

“Nonetheless, effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones. Thus, we sought to determine whether perturbation [disrupting or altering] of other pathways could improve the efficacy of MTA-cooperative PRMT5 inhibitors.”

To inform their research, the scientists analyzed genetic data from thousands of cancer patients available through the cBioPortal, an open-access resource.

They applied a gene-editing technology called CRISPR 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.

Mulvaney estimates that around five percent of all cancer patients—some 80,000–100,000 per year in the US—could benefit from the newly identified therapies.

Using PRMT5 inhibitors with drugs that block a communication system that tells cancer cells when to grow, divide or shut down the—’MAP kinase pathway’—the 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,” said Mulvaney.

As well as hopefully helping to lead to better lung, brain and pancreatic treatments, the therapy shows promise for other types of cancer. This includes melanoma—the most dangerous type of skin cancer—and mesothelioma—mainly affecting the lining of the lungs, though can also affect the lining of the stomach, heart of testicles.

In both animal models and cell cultures derived from patient tissue, lab members saw success after testing potential therapies. Mulvaney explained that in the lung cancer models, for example, 75 percent of mice ended up with no detectable tumors after treatment. These responses were stable after drug withdrawal.

“In all cases, the combination is better at killing cancer cells than the single agents,” she said. “Only the combinations led to complete regressions.”

Mulvaney explained further, “We’ve only tested dosing concurrently in preclinical models. It will be interesting to test whether the drug dosing order matters e.g., if we can treat with one compound before adding the other for further benefit or whether concurrent dosing is better.”

Could there be increased side effects from the new therapy? “In the preclinical mouse models, the combination dosing was well tolerated; no weight loss was detected in the mice. It will be important to monitor potential side effects of the combination in the clinical trials.”

The researchers concluded in the paper, “Overall, this study identifies therapeutic combinations with MTA-cooperative PRMT5 inhibitors that may offer significant benefit to patients.”

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Reference

Knoll, N., Masser, S., Bordas, B., Ebright, R. Y., Li, G., Kesar, D., Destefanis, E., Kania, N., Rodriguez, D. J., Jen, J., Zagar, S. E., Mensah, C., Chen, Z., Moffitt, S. J., Enakireru, E. M., He, Y., Feng, B., Chokshi, M. K., Jin, C. Y., … Mulvaney, K. M. (2025). CRISPR-Drug Combinatorial Screening Identifies Effective Combination Treatments for MTAP-deleted Cancer. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-25-1464