Researchers believe they have discovered why treatment of advanced prostate cancer so often fails after months or even years of what seems like success. The cancer cells, they found, respond to treatment by generating extra copies of a gene that helps fight off the therapy's destructive effects on the tumor.
The basic treatment for advanced prostate cancer is androgen deprivation, a dramatic reduction in the male hormones that stimulate tumor growth. A team of researchers from Finland and the National Human Genome Research Institute (NHGRI), a component of National Institutes of Health (NIH), found that after this treatment, tumor cells often exhibited multiple copies of the gene encoding the androgen receptor (AR), which binds the hormone to the cell. Tumors taken from the same patients before treatment contained only the usual single copy of the gene, they announced today in the April issue of Nature Genetics.
The scientists suggest that the AR gene is amplified during androgen deprivation therapy because additional copies of the gene help tumor cells soak up what little hormone is available, and so keep growing even when androgen concentrations are low. Overexpression of amplified genes often accompanies acquired resistance to cancer therapies in vitro, but this is the first time the mechanism has been implicated in tumor progression in patients undergoing treatment.
"These findings tell us that some recurrent prostate cancers are highly dependent on low levels of androgen," said Tapio Visakorpi, M.D., Ph.D., the paper's lead author and NIH visiting scientist who conducted the study. "We may need to look more carefully at whether complete androgen blockage is helpful for some people with prostate cancer."
Androgens, which include the hormone testosterone, produce the secondary sex characteristics of males. The testes secrete about 95 percent of the body's androgens, while the adrenal gland generates the rest.
Testicular androgens, in particular, play an important role in some cancers of the prostate, the small male gland near the bladder that helps liquify semen. Because many prostate cancers cannot be removed surgically, doctors often advise their patients to undergo hormone therapy or removal of the testes to block testicular androgens from the tumor. While this treatment does not cure the disease, a recent study showed it does produce temporary and at least partial remission in up to 80 percent of newly diagnosed patients.
But once treatment fails in a few months or years, long-term patient survival is poor. Indeed, over 32,000 American men die each year from prostate cancer, making it the second-leading cause of cancer death in males.
These grim statistics have sparked a longstanding debate about whether total androgen shut down, including adrenal androgens, would hold the cancer in check longer. Clinical trials have suggested some survival benefits. But they are associated with higher treatment costs and increased side effects.
Today's findings offer compelling new evidence to the debate. Dr. Visakorpi and his colleagues at Tampere University Hospital found that the androgen receptor (AR) gene was overproduced, or amplified, in several recurrent human prostate cancers. Androgen receptors are proteins that bind androgen and help the hormone signal the DNA to produce specific proteins.
The group found that the AR gene was amplified in seven of 23 recurrent tumor samples. Amplification rates varied, ranging from 3.8 to 21.5 gene copies per cell. In one case, 40 AR copies were detected in a tumor cell. Normally, cells have just one copy of the AR gene.
The results are particularly striking, Dr. Visakorpi said, because he and his coworkers found that the AR gene was not amplified in tumor samples taken from these same patients prior to treatment. "It may be that just as a fisherman has a greater chance of catching a fish if he casts more than one line, androgen-dependent cancer cells increase their chances of binding androgen by generating more receptors," explained Dr. Visakorpi.
Dr. Visakorpi said total androgen blockage might not be helpful for all prostate cancer patients. But DNA screening tests, he suggested, could be used to target those who amplify the AR gene and so might benefit from total androgen blockage.
Today's results also provide an excellent case study of how genome science is helping to offer new insights into old clinical problems. The researchers began screening the DNA from recurrent prostate cancer samples, hoping to identify an unusual molecular event linked to the tumor. They soon found increased gene activity on the long arm of chromosome X. Based on previous genome studies, the researchers knew the AR gene was located on this region of the chromosome and decided to focus their attention there. By using a fluorescently labelled AR gene probe, the scientists were able to generate today's results in a matter of months.
"The most important point is we would have never looked for AR gene amplification unless we already knew that the gene was there," said Olli-P. Kallioniemi, M.D., Ph.D., of Tampere University Hospital and one of the paper's authors. "I don't know if we could have done it otherwise. It would have taken years even to find the AR gene."
Jeffrey Trent, Ph.D., director of NHGRI's Division of Intramural Research, agreed with Dr. Kallioniemi, adding that today's findings also have significance for the study of other human cancers. "This work offers an exciting glimpse into the molecular basis of human cancer," he said. "By investigating AR amplification further, we can begin to pose even more fundamental questions about the role of gene amplification in the cancer process."
The National Human Genome Research Institute is a component of the National Institutes of Health, which is part of the U.S. Department of Health and Human Services.
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Last Reviewed: May 10, 2010