In the Journals

Genetic mutation identified in castration-resistant prostate cancer

Researchers have identified a mutation in the androgen-synthesizing enzyme 3(beta)-HSD1 in castration-resistant prostate cancer, which allows the tumor to create its own supply of androgens.

“For patients with advanced prostate cancer, treatment can include testosterone deprivation therapy, which works most of the time, but then the tumors invariably become resistant,” Nima Sharifi, MD, Kendrick family chair for prostate cancer research at Cleveland Clinic, told HemOnc Today. “When the tumors do become resistant, they acquire the ability to synthesize their own supply of DHT, or dihydrotestosterone, which is the most potent androgen. Although this has been known for awhile, no one has ever described any mutations that are responsible for driving DHT synthesis or any mutations in steroid-synthesizing enzymes in particular.”


Nima Sharifi

The 3(beta)-HSD1 mutation occurs within castration-resistant prostate cancer tumors and can come from germline DNA, inherited from both maternal and paternal sources.

Sharifi and colleagues assessed the time to the development of castration-resistant prostate cancer of xenograft tumors in orchiectomized mice supplemented with dehydroepiandrosterone intended to mimic human adrenal physiology.

According to study results, laboratory models of human prostate cancer fell into two categories of androgen synthesis: those that produce androgens gradually and those that produce them quickly. The researchers found that the 3(beta)-HSD1 mutation was the decisive factor in causing the enzyme to become hyperactive in producing androgens.

“This is the first mutation discovered that is responsible for increasing DHT synthesis to drive castration-resistant prostate cancer, and it may lead to the development of both biomarkers for detection of this mutation in clinical tumors, as well as the clinical development of pharmacologic inhibitors against this enzyme,” Sharifi said. “This kind of strategy is the crux of personalized medicine that is currently used as the standard of care for some forms of lung cancer and melanoma.”

Disclosure: The researchers report no relevant financial disclosures.