The body's immune system fends off more threats than we may ever realize. It is remarkably successful in keeping us healthy. But in diseases such as prostate cancer, the immune system is sabotaged in insidious ways. One culprit is a protein called CDK5. In mouse studies, Barry Nelkin, Ph.D., professor of oncology, has discovered that deleting the CDK5 gene in prostate cells provides a hefty boost to the body's immune system and dramatically lengthens survival.
Nelkin believes this research has the potential to help prolong life in men with metastatic prostate cancer. Advanced cancer cells are difficult to kill for many reasons; one is that cancer-fighting drugs target tumors in very specific ways, and don't always have the same effect in every man. "There is an urgent need for better therapies for advanced prostate cancer that can be applied to the majority of patients," says Nelkin. "Immunotherapy, because it targets the body's immune response rather than a specific feature of the tumor itself, has the potential to fill this need."
Think of a situation in nature where an invasive plant or insect has no natural predators, and disaster results. In cancer, the natural balance is thrown off in two major ways: An invasive set of cells is introduced, and the body's ability to kill it is compromised. Scientists have long been excited about the potential of immunotherapy to boost the body's own defenses so that it can fight off cancer, but despite tremendous advances in this field, there has been no "home run" immunotherapeutic drug that has managed to succeed against prostate cancer. "Improvements in the efficacy of immune modulation for anti-tumor response are critically needed," says Nelkin. He believes that new approaches, including combining forms of therapy, may have better success. "Our preliminary data shows the exciting prospect of such a new approach to immunotherapy – modulating the immune response by targeting signaling pathways within the tumor cells."
With support from the Patrick C. Walsh Prostate Cancer Research Fund, Nelkin is pursuing his lab's exciting early findings that suggest targeting CDK5 may be the way to go. In mouse models, "we have found that prostate-specific deletion of the CDK5 gene resulted in a dramatic survival benefit." After treatment, the prostate tumors in these mice "unexpectedly showed significant differences in expression of a variety of genes related to inflammation and immune response," including immune system-stimulating proteins that regulate T cell function. T cells are elite immune system warriors, powerful lymphocytes, or white blood cells, that protect against infection. "When we deleted the CDK5 gene, there was a dramatic activation of T lymphocytes compared to mice in the control group," says Nelkin. "These findings suggest that the impressive tumor-suppressive effects of getting rid of the CDK5 gene in the prostate may be happening, at least in part, because the antitumor immune response has been turned up."
Nelkin is now working to understand the specifics of how this works in detailed further studies. If this form of immunotherapy is as successful as Nelkin envisions, it could lead to a new form of therapy for prostate cancer, "in which CDK5 would be inhibited pharmacologically, likely followed by further specific modulation of the anti-tumor immune response. If our hypothesis is correct, rapid translation to applying this in men with prostate cancer is possible, since drugs that inhibit CDK5 are already in clinical trials."