Researchers identify possible cause of castration-resistant prostate cancer

By Peter Wehrwein

Testosterone promotes the growth and spread of prostate cancer cells. That’s why advanced prostate cancer can be managed with hormonal therapy that drives down production of testosterone in the testicles. But almost invariably, the cancer eventually breaks through and starts growing again. Such breakthrough disease is called castration-resistant prostate cancer.

A research group led by the Cleveland Clinic’s Nima Sharifi has identified an enzyme that may be the escape hatch that advanced prostate cancer uses to evade hormone therapy. If the findings hold up, the enzyme might be a prime target for a drug that would treat castration-resistant prostate cancer.

A male hormone more potent than testosterone

The enzyme that Sharifi and his colleagues identified has one of those more-than-a-mouthful names—3β-hydroxysteroid dehydrogenase type 1. It’s usually referred to by the slightly less intimidating soup of initials, 3βHSD1.

Using cell lines, mice, and DNA from the tumors of men with castration-resistant prostate cancer, they laid out several, interlocking lines of evidence to make case for an altered version of 3βHSD1 being pivotal in the development of castration-resistant prostate cancer.

3βHSD1 is crucial to a complicated process that converts dehydroepiandrosterone (DHEA), a hormone produced by the adrenal glands, into dihydrotestosterone (DHT). Like testosterone, DHT is a male hormone. It is more potent in many respects than testosterone, especially as a hormonal provocateur of prostate cancer cell proliferation.

Normally, smaller proteins glom on to 3βHSD1, altering its shape and function. Sharifi and his group identified an altered form that resists those changes. More intact 3βHSD1 in circulation means more DHEA gets converted into DHT, which prods prostate cancer cells to proliferate—even if hormone therapy has ratcheted down testosterone levels so other go-forth-and-multiply signals are lacking. The result: castration-resistant prostate cancer.

The results were reported in the Aug. 29, 2013, edition of the prestigious scientific journal Cell.

Could this lead to targeted treatment for prostate cancer?

Several new treatments for castration-resistant prostate cancer have been developed recently, so it’s far from hopeless, but castration-resistant prostate cancer is a late-stage cancer that remains very difficult to treat.

Where exactly the research on 3βHSD1 might go is hard to say. In their Cell article, the researchers pointed to other cancer drugs that are tailored to certain mutations, which may set a precedent for 3βHSD1-targeted drugs for castration-resistant prostate cancer. No such drugs exist now. And it is long shot to go from identifying what might be a cancer’s Achilles’ heel to developing a medication that can reliably hit it.

Still, we are in the age of targeted cancer treatment, and to have one for prostate cancer would be a big advance.