Genetic mutation discovered in castration-resistant prostate cancer

New research has found that the androgen-synthesizing enzyme 3βHSD1 has a mutation that enables a tumor to make its own supply of androgens, which are the hormones that fuel the growth of prostate cancer.

Prostate cancer requires a constant supply of androgens in order to sustain itself. The current standard of care for patients with metastatic prostate cancer is medical castration, which uses medications to disrupt the body's production of testosterone (androgens). Oftentimes, metastatic prostate cancer flourishes despite the lack of testosterone in the bloodstream, creating castration-resistant prostate cancer (CRPC). These tumors are able to exist without the body's supply of testosterone by creating androgens within the tumor cell; however, increased androgen synthesis has not yet been attributable to any known mutations. This discovery, published in Cell (2013; 10.1016/j.cell.2013.07.029), shows that the 3βHSD1 mutation makes this enzyme hyperactive to create androgens.

"This discovery gives us the ability to identify molecular subtypes of prostate cancer known to resist treatment. By finding the mutated enzyme, we can now investigate treatments that block it. This kind of strategy is the crux of personalized medicine, which is currently used as the standard of care for some forms of lung cancer and melanoma," said lead investigator Nima Sharifi, MD, Kendrick Family Chair for Prostate Cancer Research at the Cleveland Clinic in Ohio.

The 3βHSD1 mutation can occur within CRPC tumors and it can also come from germ line DNA, which is inherited from maternal and paternal sources.

The research found that laboratory models of human prostate cancer fall into two categories of androgen synthesis: those that make androgens slowly and those that do so rapidly. Next, they found that the 3βHSD1 mutation explains the difference between these two categories and that DNA from some patient tumors also contains this mutation. The mutation works by opening the floodgates to androgen synthesis, essentially, throwing fuel on the fire that promotes tumor progression.

In an era of personalized cancer care, there is increased focus on defining and treating cancer by its genetic abnormalities. Tumor-promoting enzyme mutations in several cancers have been identified and, subsequently, have led to the development of targeted drug therapies, improving outcomes for patients.

"The past decade has seen an explosion of molecularly targeted therapies that are matched to specific mutations in a given patient's tumor," said Sharifi. "However, no drug-targeting based on enzyme mutations exists for the standard treatment of metastatic CRPC. With this finding, we have the opportunity for matching a mutant disease-driving biomarker with a pharmacologic inhibitor."
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