Prostate-Cancer Find Points To New Drug Target

Doctors have long known that the medications they use to treat prostate cancer effectively for one to two years inevitably fail, leaving patients with few treatment options as the disease progresses, killing more than 30,000 men in the United States alone every year.

Now scientists have discovered that at least one such medication has a completely unexpected side effect: The compound actually turns on a molecule known to cause cancerous cells to grow. The work, which earned an award for outstanding research from the American Urological Association, is described in the November 1 issue of the journal Cancer Research.

"It's a real surprise, that the same compound that kills cancer cells also makes them grow," says Chawnshang Chang, Ph.D., corresponding author and director of the George Whipple Laboratory for Cancer Research at the University of Rochester Medical Center. "The effect of the drug reverses completely."

Treatment for men whose prostate cancer has spread to other parts of the body takes advantage of a unique characteristic that makes prostate cancer cells vulnerable: Usually they depend on testosterone for survival. When doctors slash the supply of the hormone, most of the cancer cells die.

After surgery, radiation, and other treatment options, doctors try chemical or surgical castration or hormonal therapy, which knocks out most of a man's supply of testosterone. Oftentimes, to prevent the little remaining testosterone from feeding the cancer, doctors supplement this treatment with a drug known as an anti-androgen, which blocks the molecule through which testosterone works, the androgen receptor.

But some cancer cells survive, and for reasons that doctors have not understood, after one or two years the cancer cells are no longer vulnerable to the drugs and begin growing again. Typically, doctors remove the patients from the anti-androgen, and patients improve temporarily before the cancer takes over again.

In 1998 Chang discovered the first molecular evidence of just how such drugs can actually spur prostate-cancer cells to grow under certain conditions.

Yi-Fen Lee, Ph.D., now an assistant professor in the Department of Urology, began working with Chang to see exactly how the switch takes place. Lee studied cancer cells from four men, comparing the cells from early in their disease to their cells after hormonal therapy became ineffective. The team, which included Lee, Chang, and graduate student Wen-Jye Lin, found a molecule known as MAP kinase at much higher levels in the cells that had survived hormone therapy.

Then Chang and Lee found that, in addition to cutting off testosterone by targeting a protein known as the androgen receptor, the anti-androgen also turns on MAP kinase -- a molecule which promotes cell growth and is known to play a role in diseases like breast and prostate cancer.

The finding explains at least part of the reason why drugs like hydroxyflutamide, the anti-androgen the team studied in the Cancer Research paper, suddenly switch from being effective to being ineffective. It's a surprise, the scientists say, that the compound triggers molecular signals that don't involve the androgen receptor, which has long been the main target of prostate-cancer drug treatments.

"In all of the more than 30,000 men who die of prostate cancer each year, the cancer cells have become capable of growing even when we starve the cells of testosterone," says Edward Messing, M.D., professor and chair of urology who treats hundreds of men for prostate cancer each year. "In each one of those men, there's been a fundamental change, so that the molecule we've targeted for stopping the cancer is no longer involved in the disease. It's at this point that the disease becomes a killer. Finding an additional potential target for preventing this switch is surprising and significant."

Despite the drawbacks, the scientists stress that current treatment, including hormonal therapy, is currently the best option for patients whose cancer has spread beyond the prostate gland.

"These drugs are necessary for patients who otherwise have few options," says Lee. "However, these findings do raise some concerns that should be investigated further. Perhaps these findings will help lead to a new drug target so that men with this disease can be treated more effectively."

Working on the project besides Chang, Lee, Lin, and Messing were Jiaoti Huang, Ph.D., assistant professor of pathology and laboratory medicine; Franky Chan of the Chinese University of Hong Kong; and medical oncologist George Wilding of the University of Wisconsin. The research was funded by the National Institutes of Health.