Antagonists of Growth Hormone-Releasing Hormone Inhibit Advanced Prostate Cancer

Prostate cancer is the second leading cause of death from cancer in men in most Western nations. Managing the disease in advanced cases is especially problematic because of severely limited treatments. Therefore, novel therapies are critically needed. A team of Miller School physician-scientists has demonstrated that an antagonist of growth hormone-releasing hormone (GHRH) has the ability to suppress the progression of late stage prostate cancer. The findings are published in the January 16 online edition of the Proceedings of the National Academy of Sciences.

Castration-resistant prostate cancer is a late-stage prostate cancer that has lost its sensitivity to hormonal control. Docetaxel, the most active chemotherapeutic agent, provides only a modest survival advantage and most patients eventually progress because of drug resistance.

Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that stimulates secretion of the growth hormone from the pituitary gland. Growth hormone then stimulates the production of an insulin-like growth factor that is a potent trigger for cell growth in many cancers. That effect has made GHRH an attractive target for anti-cancer therapies.

For approximately twenty years, Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., the 1977 Nobel Prize winner for Physiology or Medicine, Distinguished Medical Research Scientist of the Department of Veterans Affairs, and Distinguished Professor of Pathology, a senior author of this study, has led his laboratory in synthesizing GHRH antagonists for therapeutic use in managing various cancers.

Working with mouse models, first author Ferenc G. Rick, M.D., Ph.D., research assistant professor of pathology at the Miller School, and member of the Endocrine, Polypeptide and Cancer Institute at the Miami Veterans Affairs Medical Center, co-senior author of the study, Norman Block, M.D., professor of pathology, urology, oncology and biomedical engineering and the L. Austin Weeks Family Professor of Urologic Research, and the team demonstrated that one of those GHRH antagonists (JMR-132) significantly inhibited the growth of experimental human androgen-independent prostate cancer.

“We have seen in previous studies,” says Schally, “that this antagonist can affect the pathways of the released growth hormone. This finding validates a closer examination at its potential as a therapy.”
The findings also “showed that GHRH is a potential growth factor in prostate cancer and facilitates its proliferation,” says Rick. “This potent antagonist, JMR-132, eliminated that factor.”

Block adds that they plan evaluations of still more potent GHRH antagonists. “We expect to develop a clinical trial, hopefully soon, to convert this much newer and more effective class of compounds into an even more superior therapeutic tool for prostate cancer.”

In addition to Rick, Schally and Block, other co-authors of the study include Mehrdad Nadji M.D., professor and vice chair of pathology, and Marta Zarandi, Ph.D., D.Sc., visiting professor of pathology. Collaborators at the Miami Veterans Affairs Medical center were Luca Szalontay, M.D., assistant professor of pathology, Karoly Szepeshazi, M.D., Ph.D., voluntary professor of pathology, and Florian Hohla, M.D., Stefan Buchholz, M.D., and Stephan Seitz, M.D., all visiting assistant professors of pathology.

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