Testosterone in Prostate Cancer - New Way to Block Hormones

There’s a new way to stop the hormonal effects of testosterone, thanks to UCSF neurologist Marc Diamond, MD. Diamond studies the androgen receptor. The androgen receptor (“andro” means man) relays the male hormone’s signal to the interior of cells. Why would one want to block testosterone? And what business is testosterone to a neurologist? Testosterone loss is not something men generally look forward to. But for men with aggressive prostate cancer, sometimes blocking male hormones is the only hope. In fact, preventing testosterone production or blocking its hormone activity is a valued treatment not only for advanced prostate cancer, but also for male pattern baldness and benignly enlarged prostates. Male hormones – androgens – are implicated in other medical conditions as well. One is a rare, inherited neuromuscular disorder that results from genetic mutation to the androgen receptor. That’s how Diamond became interested in androgen receptors. Now Diamond’s research has led to a potential new target for prostate cancer treatment, a disease that kills more than 30,000 US men each year. Androgens – namely testosterone and its more potent form, DHT – stimulate prostate cancer growth. There are drugs that block testosterone production – a kind of chemical castration. There also are drugs that compete with testosterone. These drugs attach to the hormone’s site of connection to the androgen receptor. In doing so, these antagonist drugs prevent the hormone from connecting properly. This, in turn, prevents the hormone signal from being received. But these drugs often fail men with advanced prostate cancer within a year or so. The cells’ production of androgen receptor ramps up dramatically or the receptor mutates, so that the receptors again begin to transmit hormone signals, even when little testosterone is present or despite treatment with hormone antagonists. Diamond and UCSF postdoctoral fellow Jeremy Jones, PhD, now have found that a drug first used to treat a parasite more than a half century ago may have promise for prostate cancer. They made the discovery using a new drug-screening technique to identify drugs that block androgen receptor activity in a completely different way than drugs now used for that purpose. Diamond, Jones and their research colleagues reported their findings on April 10 in the early online edition of the Proceedings of the National Academy of Sciences (PNAS). Diamond adapted a technique called fluorescence resonance energy transfer to tag the androgen receptor with two differently colored fluorescent proteins. The research team tracked changes in fluorescent light emission corresponding to changes in receptor shape, and identified drugs that block critical testosterone-induced shape changes in the receptor that are required for relaying the hormone signal. One of the promising candidates identified was pyrvinium, a drug approved by the Food and Drug Administration, which was used until recently to treat pinworm, an intestinal parasite. The researchers used mice to test the anti-androgen activity of pyrvinium. The drug was as effective as chemical castration in stopping testosterone signaling. The scientists also showed that the combination of pyrvinium and the competitive antagonist bicalutamide (Casodex) blocks androgen signaling better than either drug alone. “The results indicate that pyrvinium, or a derivative, could someday be used to augment the power of classical competitive antagonists in the treatment of prostate cancer,” Diamond says. Pinworm patients who used pyrvinium swallowed it in liquid form. It goes to the gut, but it is not taken up into the bloodstream to circulate to other parts of the body. Therefore, to block testosterone signaling in the studies reported in PNAS, the researchers injected the pyrvinium into the mice. Pyrvinium blocked testosterone signaling at a very low, “nanomolar” dosage. More recently, Jones and colleagues at the UCSF Small Molecule Discovery Center altered the chemical form of pyrvinium slightly. They thereby succeeded in creating a potential drug that is active when taken orally. Diamond is exploring options for taking the research to the next phase – preclinical studies on animals.

Non-Competitive Androgen Receptor Inhibition
in Vitro and in Vivo

Jeremy O. Jones, Eric C. Bolton, Yong Huang, Clementine Feau, R. Kiplin Guy, Keith R. Yamamoto, Byron Hann and Marc I. Diamond
Proceedings of the National Academy of Sciences (Published online April 10, 2009)
Abstract | Full Text (PDF)

Related Links:

Diamond Lab at UCSF

Helen Diller Family Comprehensive Cancer Center