Reason for failure of hormonal therapy of prostate cancer

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The hormone deprivation treatment that patients with prostate cancer often take gives them only a temporary fix, with tumors commonly regaining their hold within a couple of years. Now, scientists at Johns Hopkins have discovered critical differences in the hormone receptors on prostate cancer cells in patients who no longer respond to this treatment. The findings, published in the Jan. 1 issue of Cancer Research, could lead to a way to track disease progression, as well as new targets to fight prostate cancer.

Prostate cancer cells rely on androgens, male hormones that include testosterone, to survive and grow, explains Jun Luo, Ph.D., an assistant professor at Johns Hopkins' James Buchanan Brady Urological Institute. Since 1941, doctors have taken advantage of this dependency to battle prostate cancer by depriving patients of androgens, either by castration or chemical methods. For most patients, this hormone deprivation treatment causes tumors to shrink, sometimes dramatically. However, it's never a curetumors eventually regrow into a stronger form, becoming resistant to this and other forms of therapy.

Seeking the reason why this treatment eventually fails, Luo and colleagues at the Johns Hopkins University School of Medicine, the University of Washington and Puget Sound VA Medical Center looked to a key player: the androgen receptors on prostate cancer cells.

Using a large database, the scientists searched for variations of the nucleic acid RNA that prostate cells use to create androgen receptors, eventually identifying seven RNA sequences different from the "normal" androgen receptor already known to scientists. When they looked for these sequences in cells isolated from 124 patients with prostate cancer, they found over-production of these outlaw variants in prostate cancer cells taken from patients whose disease had become resistant to hormone deprivation treatment. One variationknown as AR-V7, was also prevalent in a select group of patients who had never taken hormone treatment, but whose cancer aggressively regrew after surgery to remove their tumors.

To see how androgen receptors made from AR-V7 differ from others, the scientists forced lab-grown prostate cancer cells to produce only the AR-V7 sequence. Unlike cells with other androgen receptors, those with only AR-V7 receptors acted as if they were continually receiving androgensturning on at least 20 genes that rely on androgens for activationeven though no androgens were present.

The results suggest that hormone treatment might encourage prostate cancer cells to overproduce the AR-V7 receptors over time, leading them to survive and grow aggressively even without androgens, explains Luo. In some patients, he adds, AR-V7 receptors might already be prevalent even without hormone treatment, predisposing them to an already-aggressive form of prostate cancer that won't respond as well to hormone deprivation treatment.

"We may eventually be able to develop an assay to test for this androgen receptor variant, giving us a way to test which patients are good candidates for hormone deprivation treatment and providing a way to monitor disease progression in patients already on this treatment," Luo says.

Examining the differences between AR-V7 and other androgen receptor variants may also provide scientists with new ideas to develop prostate cancer-fighting pharmaceuticals, he adds.


Posted by: Mark    Source