Mar. 7, 2002 Hormone therapy is often used to treat prostate cancer, but these drugs that mimic the effects of estrogen do not work on many late-stage cancers. Now San Francisco Veterans Affairs Medical Center researchers say they can explain the failure of these drugs, and suggest a way to restore their potency.
The study, published in the latest issue of Journal of the National Cancer Institute, reveals that late-stage prostate cancer is unresponsive to hormone therapy because the cells have shut down genes for the estrogen receptors where the drugs act.
The genes are switched off by a process called hypermethylation, a well-known process in which numerous methyl groups are attached to the regulatory stretches of DNA near the beginning of the gene, said the study’s lead author Raj Dahiya, PhD, director of the urology research center at SFVAMC, and UCSF professor of urology.
“This hypermethylation explains why we see inactivation of estrogen receptors in prostate cancer, and why hormone therapy no longer works in many cases,” said Dahiya, whose research was supported by funding from the Department of Veterans Affairs, and by grants from the National Institutes of Health, which were managed by Northern California Institute for Research and Education (NCIRE).
In their study, Dahiya’s group first showed that normal prostate cells were free of methylation at estrogen receptor genes and the cells displayed plenty of estrogen receptors. However, cells from late-stage prostate cancers had hypermethylation on their estrogen receptor genes and the cells displayed no estrogen receptors. Cells from an early stage prostate cancer have some methylation, which leads to intermediate activity, and the generation of relatively few estrogen receptors, Dahiya said.
Studies of prostate tissue taken from 38 prostate cancer patients further strengthened the link between hypermethylation and prostate cancer. The researchers found that nearly all tissue samples from tumors had hypermethylation on their estrogen receptor genes, but tissue samples from healthy sections of the prostate showed no such methylation.
Genetics researchers have studied hypermethylation for years, Dahiya said, and they know how to prevent it. This raises the hope that tumors that are resistant to hormone therapy could be made vulnerable again.
In fact, Dahiya and his colleagues treated some of their prostate cancer cells growing in culture with a drug that reverses methylation, and the cells once again switched on their estrogen receptor genes.
“People are testing de-methylating agents in clinical trials for several other cancers. In prostate cancer we could inject these drugs directly into the prostate, and that might restore the lost effectiveness of hormone therapy,” he said.
This study should serve as the basis for future clinical trials of demethylating agents for prostate cancer, said Peter Carroll, MD, chair and professor of the UCSF Department of Urology.
Co-investigators on the study included Masahiro Sasaki, MD, PhD, a research scientist at UCSF/SFVAMC; Yuichiro Tanaka, PhD, associate investigator at UCSF/SFVAMC; Geetha Perinchery MD, fellow at UCSF/SFVAMC; Abhipsa Dharia, MD, fellow at UCSF/SFVAMC; Ioulia Kotcherguina, MD, fellow at UCSF/SFVAMC; and Sei Ichiro Fujimoto, MD, PhD, professor of obstetrics and gynecology at Hokkaido University, Japan.
NCIRE is one of the fastest growing medical research groups in the nation. Founded in 1988, NCIRE now manages more than $30 million in funding from organizations such as the National Institutes of Health, Department of Veterans Affairs, the National Aeronautics and Space Administration, and the National Science Foundation. Based at the San Francisco VA Medical Center, NCIRE is the largest of the 80 congressionally authorized VA research corporations.
The San Francisco Veterans Affairs Medical Center has been a primary affiliate of University of California, San Francisco since 1974. The UCSF School of Medicine and the SFVAMC collaborate to provide education and training programs for medical students and residents at SFVAMC. SFVAMC maintains full responsibility for patient care and facility management of the medical center. Physicians at SFVAMC are employed by the Department of Veterans Affairs and also hold UCSF faculty appointments.
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