Blocking Metastasis, Protecting Bone

Metastasis, the spread of cancer past the point of treatment, is what kills men with prostate cancer. Somehow, scientists must learn how to block metastasis, which is a complicated process, with many steps. But if metastasis is a railroad track for cancer, maybe scientists don't need to dismantle the entire track to derail the train. Maybe just blocking one section will be enough.

This is what Barry D. Nelkin, Ph.D., professor of oncology, believes, and he has found a highly promising target - an enzyme called CDK5. He has been named the Nancy and Jim O'Neal scholar from The Patrick C.Walsh Prostate Cancer Research Fund to see whether stopping CDK5 will put metastasison hold. Nelkin's work on this began with a startling observation: There are "striking similarities" between the way neuronsmigrate during normal brain development, and the way cancer cells travel in metastasis."We reasoned that the underlying mechanisms of these processes might be similar,"he says. In brain development, the enzyme CDK5 controls cell migration and invasion. But he has found that CDK5 is active in the vast majority - 28 of 32 - of strains of metastatic prostate cancer he has studied.

"Genetic inhibition of CDK5 activity blocked cell motility, invasion, and, in ananimal model, reduced metastases by 79 percent," he continues, "suggesting CDK5 as a potential therapeutic target to limit metastasis in prostate cancer.

"There's good news already in this story -some CDK5-blocking drugs already exist, for treatment of neurodegenerative disease. This means that Nelkin and colleagues have hit the ground running, and are testing these drugs in laboratory animals with metastatic prostate cancer. They are also looking to develop laboratory tests to monitor CDK5 activity in prostate cancer cells.

What this means for bone: "Bone is the most significant metastatic site for prostate cancer," notes Nelkin. "Blocking CDK5, in addition to inhibiting metastasis, may also inhibit the ability of prostate cancer to survive and grow in bone." Nelkin and colleagues will be exploring this, using an animal model of prostate cancer metastasis in bone. They will also see whether blocking CDK5 makes other chemotherapeutic drugs more effective. "We envision that this could provide a therapeutic benefit, especially for patients with limited disease," he says. For example, blocking CDK5 in a man with prostate cancer that has spread only to the lymph nodes, "could prevent further progression - potentially allowing effective therapy or even cure by other forms of treatment. We speculate that clinical trials could begin within one to two years ofthe successful completion of this project."

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