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HOW DOES CANCER SPREAD TO BONE? ONE FACTOR IDENTIFIED BY U.VA. SCIENTISTS MAY BE POTENTIAL TREATMENT

Although the survival rate for prostate cancer patients is quite high, many men die from the disease when it has been detected late and the cancerous cells have spread, or metastasized, to bone.

Now, two researchers at the University of Virginia Health System, reporting in the Proceedings of the National Academy of Sciences, have identified the role of a compound that seems to be a key target for therapies meant to halt bone metastases in prostate and breast cancer patients. The study can be found online at www.pnas.org.

According to the National Institutes of Health, in many late-stage prostate cancer cases the disease spreads to the pelvic lymph nodes. From there, the cancer cells show a propensity for invading bones in the pelvis and vertebra of the lower back, leading to disorganized formation of new bone.  Similar bone metastases can be found in breast cancer patients, most typically in women, and occasionally in men.

Using animal models, the U.Va., researchers, Dr. Theresa Guise and John Chirgwin, found that a factor expressed by cancerous tumors, called endothelin-1, stimulates osteoblasts, cells responsible for the formation of new bone. The researchers identified a specific receptor on the osteoblasts that acts as a “welcome mat” for endothelin-1, leading to increased bone formation. Their study concluded that treatment with a drug that targets a receptor antagonist on the osteoblast, called Atrasentan, dramatically decreased bone metastases in mice.

“The real benefit of this study will be in prevention,” said Guise, lead author of the study, a Mellon investigator at the U.Va. cancer center and professor of endocrinology. “We can delay the progression of cancer in patients who have bone metastases, but there is no known therapy to cause regression; and once a tumor gets to bone it is incurable. We’re hopeful that the results of this study will help lead to new treatments to block metastasis to bone.”

Atrasentan (ABT 627) is now in Phase III clinical trials involving men with prostate cancer. One unique characteristic of the drug is that it has no direct effect on cancer cells. “The drug acts on bone cells by blocking the effect of cancer cells, so the treatment side-effects can be quite mild compared to chemotherapy where toxic drugs are used to kill the tumor,” said Chirgwin, study co-author and a professor of internal medicine at U.Va. “Cancer patients can live for a number of years with bone metastases, but there can be a lot of pain and bone fractures. A treatment specifically for bone metastases can give a substantial improvement in the quality of life in many patients,” he said.

Initial research for this study of the role of endothelin-1 was conducted by Guise and Chirgwin at the University of Texas Health Science Center in San Antonio, Texas. Their research continues in the Aurbach Medical Research Labs at U.Va.

August 26, 2003