A Hint Why Hormone Therapy for Prostate Cancer Ultimately Fails

June 23, 1998

The drugs commonly given to help men beat prostate cancer may actually help the cancer grow under some conditions, a University of Rochester Cancer Center team shows in a study published in the June 23 issue of the Proceedings of the National Academy of Sciences. The work provides a possible explanation for why most forms of hormone therapy, a common treatment for prostate cancer, almost always lose effectiveness after one or two years.

The team showed that drugs known as anti-androgens, often given to men to shrink the prostate and kill the cancerous cells within, can trigger the protein that makes the prostate and its cancer grow.

"It's a real shocker, and it's still quite controversial, but our experiments show that this happens," says Chawnshang Chang, lead investigator and George Whipple Professor of Pathology and Urology. "These compounds are capable of stimulating what they're supposed to be preventing." He stresses, though, that more research is needed to confirm the results, and that it's too early to consider altering the standard treatment patients receive today.

The prostate is a peach-sized organ between the bladder and rectum that contributes fluids to semen. Prostate cancer, which strikes slightly more often in men than breast cancer does in women, kills about 39,000 men in the U.S. each year. The growth of the prostate and cancerous cells there rely on the androgen receptor, the protein turned on by testosterone and other "male" hormones, known as androgens. The receptor triggers genes that give men facial hair, deep voices and other masculine traits, including prostate growth. In women estrogen hormones are responsible for developing female characteristics. While both are present in everyone's bodies, scientists have long thought that the two groups of hormones turn on very distinct sets of genes.

For several decades physicians have treated men with advanced prostate cancer with castration therapy, anti-androgens, or estrogen-like compounds to shrink the prostate. But within a couple of years the treatments lose effectiveness and the prostate starts growing again, mysteriously. Since the therapy usually comes after doctors have tried other treatment options, such as surgery, brachytherapy, or radiation, its failure often marks a turning point in the spread of the disease.

In the PNAS paper Chang and colleagues show that anti- androgenic compounds can cross the line and turn on the androgen receptor. Working with human prostate cells in a cell culture, the scientists showed that anti-androgens, including hydroxyflutamide, bicalutamide (casodex), and cyproterone acetate, can trigger the androgen receptor, which in turn spurs the growth of the prostate and its cancerous cells.

In another PNAS paper last month the team showed that estrogen can also turn on the androgen system and even seems to play a critical role in the formation of the male reproductive system. In partial-androgen-insensitivity syndrome, a person has both an X and a Y chromosome and is genetically a man, but because of a single mutation in the androgen receptor the person has severe genital abnormalities and lives as a woman. A few thousand people in the U.S have the disease. The team showed that the mutation contributes to the syndrome by knocking out estrogen's ability to turn on the androgen receptor.

Chang, a well-known expert on the androgen receptor, was the first one to clone the protein back in 1988. Last month he showed that another molecule must be present for estrogen to turn on the receptor. The molecule, known as co-factor AR70, offers a new target against prostate cancer, Chang says. AR70 is one of several androgen receptor co-factors that the team has identified as working with other molecules to turn on the androgen receptor.

"The goal is to develop a tissue-specific anti-androgenic compound," says Chang, "so that we can turn on or off the androgen system selectively. For instance, perhaps we can stimulate hair growth but not damage the reproductive system. Identifying these co-factors is a step toward such specificity."

Also working on the project, which was funded by the National Institute of Health, were post-doctoral researchers Hiroshi Miyamoto and Shuyuan Yeh of the University, and medical oncologist George Wilding of the University of Wisconsin.

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