Researchers at the University of Texas at Austin (UT) have developed a drug able to restore the effectiveness of immune cells fighting cancer, slowing tumor growth, and increasing lifespan in mouse models of melanoma, bladder cancer, leukemia, and colon cancer.
One of the most prevalent genetic abnormalities observed in multiple cancer types is the deletion of a DNA segment known as 9p21. This deletion, which occurs in 25 to 50 percent of certain cancers such as melanoma, bladder cancer, mesothelioma, and several brain cancers, has long been associated with poorer patient outcomes and resistance to immunotherapy.
Serving as a cunning defense mechanism employed by cancer cells, the deletion triggers the production of a toxic compound called methylthioadenosine (MTA), which not only impairs the normal functioning of immune cells but also sabotages the effectiveness of immunotherapies, treatments designed to improve the patient’s natural immune response against cancer. Reporting in Cancer Cell, scientists are now able to regulate MTA production leading to a more effective immune response.
“In animal models, our drug lowers MTA back down to normal, and the immune system comes back on. We see a lot more T cells around the tumor, and they’re in attack mode. T cells are an important immune cell type, like a SWAT team that can recognize tumor cells and pump them full of enzymes that chew up the tumor from the inside out,” said Everett Stone, research associate professor in the Department of Molecular Biosciences at UT and senior author of the study.
According to the researchers, the 9p21 deletion can also lead to the loss of critical genes in cancer cells, including those responsible for producing cell cycle regulators and enzymes that break down MTA. This loss allows cancer cells to proliferate uncontrollably and disarm the body’s immune response, rendering the cancer more aggressive and malignant.
“Cancer gets a two-for-one when it loses both of these genes,” Stone said. “It loses the brakes that normally keep it from growing in an uncontrolled manner. And then at the same time, it disarms the body’s police force. So, it becomes a much more aggressive and malignant kind of cancer.”
In order to make their drug—known as PEG-MTAP—more durable in the body, the scientists used a modified version of a naturally occurring enzyme responsible for MTA breakdown.
“It’s already a really good enzyme, but we needed to optimize it to last longer in the body,” Stone explained. “If we injected just the natural enzyme, it would be eliminated within a few hours. In mice, our modified version stays in circulation for days; in humans it will last even longer.”
While this breakthrough holds immense promise for cancer treatment, further safety tests are required before PEG-MTAP can advance to human clinical trial. The researchers believe, that as the research progresses, the prospect of combining PEG-MTAP with existing immunotherapies presents an exciting avenue for further advancements in cancer treatment.