A team led by researchers at The University of Texas at Austin has discovered that a new bioinspired drug restores the cancer-fighting efficacy of immune cells. In mouse models of melanoma, bladder cancer, leukemia and colon cancer, the drug slowed tumor growth, extended lifespan and improved the efficacy of immunotherapy. The research, published in the journal Cancer Cell, could change the fate of many cancer patients.
Understanding DNA Deletions
Many cancers delete a stretch of DNA called 9p21. In fact, it is the most common DNA deletion in all cancers, occurring in up to 25%-50% of certain cancers, such as melanoma, bladder cancer, mesothelioma and certain brain cancers. Scientists have long known that cancers with 9p21 deletions mean patients have worse prognosis and are resistant to immunotherapy - treatment strategies designed to boost a patient's natural immune response to the cancer.
This deletion helps cancer cells avoid detection and destruction by the immune system, in part because it prompts cancer cells to secrete a toxic compound called MTA, which impairs the normal function of immune cells and hinders the effectiveness of immunotherapy.
Pseudocolor scanning electron micrograph of an oral squamous cell carcinoma cell (white) attacked by two cytotoxic T cells (red). Source: Rita Elena Serda, Duncan Comprehensive Cancer Center, National Cancer Institute, Baylor College of Medicine, National Institutes of Health.
Potential of new drugs
"In animal models, our drug lowered the MTA back to normal and the immune system rebooted," said Everett Stone, a research associate professor in the Department of Molecular Biosciences and associate professor of oncology at Dell Medical School, who led the study. "We see more T cells around the tumor, and they are in attack mode. T cells are an important immune cell type, like a SWAT team, able to identify tumor cells and inject them with a large number of enzymes to eat the tumor from the inside out."
Stone envisions using the drug in conjunction with immunotherapy to increase its effectiveness.
The study's co-first authors are Donjeta Gjuka, a former UT postdoctoral fellow who is now a scientist at Takeda Oncology, and Elio Adib, a former Brigham and Women's Hospital and Dana-Farber Cancer Institute postdoctoral fellow who is now a resident at Massachusetts General Brigham Hospital.
Understand the genes affected by deletions
Loss of 9p21 leads to the deletion of some key genes in cancer cells. A pair of genes that produce cell cycle regulators, proteins that keep healthy cells growing and dividing at a slow, steady rate, disappeared. When these genes are lost, cells can grow uncontrollably. This is why they cause cancer. Also deleted was a housekeeping gene that produces an enzyme that breaks down the toxin MTA. Stone believes that the loss of this gene gives cancer cells a new superpower: the ability to deactivate the immune system.
"When a cancer cell loses these two genes, it gets the best of two birds with one stone," Stone said. "It loses the brakes that normally prevent it from growing out of control. At the same time, it disarms the body's police force. So it becomes a more aggressive and malignant cancer."
To create the drug candidates, Stone and his colleagues first used enzymes naturally produced by the body that help break down MTA, and then added flexible polymers.
"This is already a very good enzyme, but we need to optimize it so that it lasts longer in the body," Stone said. "If we just inject the natural enzyme, it would be excreted within a few hours. In mice, our modified version survives in the circulation for days; in humans, it survives much longer."
The researchers plan to conduct more safety testing of their drug, called PEG-MTAP, and are seeking funding to move it into human clinical trials.