Hypoxia’s Role in Hormone Therapy Resistance and Prostate Cancer

Article Summary
  • Prostate cancer researcher Nima Sharifi, M.D., is studying the 3βHSD1 enzyme to identify ways to slow androgen production and, correspondingly, prostate cancer progression.
  • Dr. Sharifi’s work hopes to address the gradually decreasing effectiveness of hormonal therapy for prostate cancer patients.
  • Dr. Sharifi and researchers found that prostate tumors exposed to low levels of oxygen produce androgens quickly. The team is now looking for ways to counter resistance mechanisms.

Hormone therapy is a mainstay for treating prostate cancer. But patients almost always develop a resistance that allows cancer to progress to a lethal form.

“Hormonal therapy in prostate cancer therapy basically suppresses androgens, or male hormones, because prostate tumors thrive off of those male hormones,” said Sylvester Comprehensive Cancer Center researcher Nima Sharifi, M.D. “The challenge is that hormone treatments work for a while but, with time, the tumors actually start to make their own androgen.”

Prostate cancer cell shown in a electron micrograph
Hormone therapy that suppresses male hormones is often initially effective for prostate cancer patients, but its effectiveness wanes when tumors start producing androgens.

Dr. Sharifi, also scientific director of the University of Miami Miller School of Medicine’s Desai Sethi Urology Institute (DSUI), is senior author of new research published in Cell Reports that helps explain the reasons for hormone therapy resistance and the patients at greatest risk to develop resistance.

Genetic Link to Hormone Therapy Resistance

Previously, Dr. Sharifi and colleagues identified two genetic subsets of men. One group produces androgens quickly due to their inherited DNA. The other makes androgens more slowly. The discovery revealed genetics’ role in clinical outcomes. Men who produce androgens more quickly may resist therapy and die more quickly than men who do not have the same inherited genetic machinery.

Sylvester Comprehensive Cancer Center researcher  Dr. Nima Sharifi
Sylvester Comprehensive Cancer Center researcher Nima Sharifi, M.D., is studying ways to manipulate the 3βHSD1 enzyme’s stability and deter hormonal therapy resistance in prostate cancer patients.

“Our new paper addresses the subset that makes the androgens more quickly,” Dr. Sharifi said.

Researchers focused on the 3βHSD1 enzyme expressed in peripheral tissues, including the prostate, placenta, skin and mammary gland.  

3βHSD1 stabilization increases androgen production and promotes prostate cancer progression after patients have been on androgen deprivation therapy. Hypoxia is a known hallmark of prostate cancer tumor progression.

“What we found in the lab, essentially, is that, if those tumors are exposed to hypoxia, the low levels of oxygen can enable this effectively fast enzyme 3βHSD1 that allows tumors to regenerate androgens more quickly,” Dr. Sharifi said.

Studying the 3βHSD1 Enzyme

Now Dr. Sharifi’s lab is studying the 3βHSD1 enzyme’s basic mechanisms to determine how to best manipulate its stability.

“We’re looking at how to potentially reverse that process with drugs or other approaches to counter the resistance mechanisms,” he said. “Drug development is a major part of our current efforts. We’re also very interested in what this means not just for prostate cancer but other diseases that depend on sex steroids, like breast cancer.”

Tags: Dr. Nima Sharifi, hypoxia, prostate cancer, Sylvester Comprehensive Cancer Center