Dr. Nima Sharifi Pens JAMA Commentary on Prostate Cancer Variant His Team Identified

Newswise — Desai Sethi Urology Institute (DSUI) Scientific Director Nima Sharifi, M.D., authored an invited commentary in JAMA Network Open related to a new Million Veteran Program study on the HSD3B1 genotype, an allele he helped discover more than 10 years ago.

Dr. Lina Schiffer also co-authored the commentary.

Gene Variant’s Impact on Prostate Cancer Outcomes

The new study demonstrates the foundation of Dr. Sharifi’s early research showing how the variant works and suggesting that men who inherit the variant tend to have worse prostate cancer outcomes.  

Dr. Sharifi, a member of Sylvester Comprehensive Cancer Center, authored a paper in Cell in 2013 before joining DSUI. He and his team showed the adrenal-permissive HSD3B1 allele stimulates local production of active androgens in prostate cancer.

His team’s studies and several others since have shown that the 7 to 10% of men with prostate cancer who have the adrenal-permissive genotype (1245C) in the HSD3B1 gene are more likely to rapidly develop castrate-resistant disease and have worse outcomes.

Prostate cancer’s progression depends on androgen receptor signaling. Treatment with androgen deprivation therapy (ADT) (hormone therapy) exploits this dependency. But having 1245C in the HSD3B1 gene promotes ADT resistance and stimulates local production of active androgens in prostate cancer.  

Million Veteran Program Study

Researchers at the Million Veteran Program led the new study, looking at 5,287 veterans. Study participants who had 1245C in the HSD3B1 gene had a five-year incidence of prostate cancer-specific mortality of 4.0% compared to 1.9% for other genotypes.

Men with this genotype also had more fatal disease and progressed from metastatic disease to prostate cancer death more than 2.4 times faster.

“This is a large, ethnically diverse study of prostate cancer patients,” Dr. Sharifi said. “Now we can say with much greater confidence that this finding is clinically meaningful, as HSD3B1 status can inform prognosis and response to hormone therapy. Indeed, HSD3B1 appears to be the most common monogenic driver of prostate cancer mortality.”

Looking for New Treatments

Researchers including Dr. Sharifi have looked at several ways to target the enzyme and eventually treat some men at increased risk of poor outcomes from prostate cancer.

“Together, we have designed a clinical trial that uses this aspect of genetics to select men who may benefit from these treatments,” Dr. Sharifi said.

In the meantime, Dr. Sharifi recommends HSD3B1 genetics be noted in all men with prostate cancer, even if they’re not receiving hormone therapy.

“The new paper’s authors also found that detection of this gene in men who had non-metastatic prostate cancer puts them at elevated risk for dying from the disease,” he said. “And, because it’s a gene that confers resistance to hormonal therapy, it may help direct therapies very early on. Obviously, a lot more work needs to be done, but I think the data that’s coming out is indeed powerful.”