Researchers receive grant to study prostate cancer

Researchers at the University have received $5 million from the National Cancer Institute and the National Institute on Aging to investigate prostate cancer, the second leading cause of cancer deaths among men in the United States. This year, 37,000 U.S. men will die from the illness, according to the American Cancer Society, and 179,300 new cases will be diagnosed.

Specifically, the School of Medicine scientists will investigate mechanisms responsible for reappearance of hormone-independent prostate cancer in patients following treatment to remove the source of androgen. They also will investigate why black men develop prostate cancer twice as often as white men do.

Answering those questions should provide solid clues to the illness that will benefit both races, the scientists say.

"Prostate cancer requires male hormones known as androgens both to develop and to grow, and the same is true for benign prostate tissue," said James L. Mohler, associate professor of surgery. "One big difference is that cancer can spread, which obviously can make it fatal.

"Another is that if you take androgens away from a man with a benign but enlarged prostate, the prostate shrinks and stays small for the rest of his life," Mohler said. "With prostate cancer, however, if you take androgens away, the tumor goes into remission but will come back after several years having acquired the ability to grow again even without androgens."

Researchers want to determine how the cancer can grow without male hormones. Such information might enable them to cure prostate cancer just by preventing its re-growth, the surgeon said.

The new grant, a highly competitive award known as a program project, will cover five years of work, said Mohler, who is principal investigator and a member of the Lineberger Comprehensive Cancer Center.

Others involved include Frank S. French, professor of pediatrics and director of the Laboratories for Reproductive Biology; Gary Smith, professor of pathology and laboratory medicine; Elizabeth M. Wilson, professor of pediatrics and biochemistry; Sharon Presnell, assistant professor of pathology and laboratory medicine; Desok Kim, research associate at the Lineberger Center; and Christopher W. Gregory, postdoctoral fellow in pediatrics and the Laboratories for Reproductive Biology.

The award will fund three projects and a core laboratory for tissue storage, staining and analysis.

Led by Mohler, researchers in the first project will investigate the role of androgen receptor -- the regulatory protein on which the androgens act -- on the ability of the cancer eventually to grow even in the absence of androgens.

"A particular focus will be on how this process is different in Caucasians and African Americans, who also are twice as likely to die from prostate cancer, even after accounting for possible differences in health care," he said.

On a molecular level, his group will explore differences in androgen levels and androgen receptors between the races, he said. Twelve North Carolinians with prostate cancer, including both blacks and whites, agreed to have their prostate glands biopsied before removal of androgens and regularly every few months until their cancers return.

"This is providing an invaluable set of specimens to follow what happens in individual patients as their cancers recur," Mohler said.

In the second project, French, Wilson and Gregory will employ a unique tumor model known as CWR-22. It consists of human prostate cancer growing in immune-deficient mice.

"If you remove the source of androgen in the mice by castration, the human prostate cancer goes into remission like in human patients and then returns about five months later and continues to grow in the absence of androgen," French said.

"We are using the model to try to determine whether the androgen receptor regulates growth even when androgen is absent. These studies are geared to develop a gene therapy approach to preventing growth in the absence of androgen."

The third project, led by Smith and Presnell, will test the hypothesis that prostate tumors contain a small population of stem-like cells that express a primitive form. These stem-like cells can be stimulated to grow by androgen, but unlike benign prostate cells or the majority of cells in the prostate tumor, such stem-like cells would not die when the supply of androgen is blocked. Surviving cells could therefore be the source of the cancer that recurs in the absence of androgen.

Funding from the program project also will support the maintenance of a repository of tissue specimens from tumors collected by the team.

Such specimens are critical for the investigations, as well as collaborative studies with other researchers at Carolina and from around the United States.

Kim will direct the Immunoanalysis Core. It will allow for sophisticated analysis of genes and proteins in both animal and human samples through a system relying on standard and fluorescence microscopy and image analysis using software developed at the University to measure molecules of interest in prostate tissue.

"In this country, almost 40,000 men are still dying of advanced prostate cancer every year," Mohler said. "Since the 1940s when we learned that the cancer goes into remission when androgens are taken away, either by castration or medical therapy, there has not been any significant advance in the care of patients.

"If we can understand better the `switch' that turns these cancers on again, we would solve a major health care problem," he said. "We'd also prevent a lot of suffering because dying from prostate cancer is a very unpleasant death."

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