Reversing Enzalutamide Resistance Offers Promise for Treating Advanced Prostate Cancer

A research team led by Nima Sharifi, MD, Cancer Biology, has uncovered a cause of prostate cancer drug resistance and was able to reverse the resistance in human prostate cancer cells grown in a mouse model.

Resistance to prostate cancer drugs is a common clinical problem. As prostate cancer cells need male hormones, or androgens, to grow, standard therapies like androgen deprivation (or “medical castration”) can be effective for advanced prostate cancer, but they typically stop working at some point. When standard therapies fail, patients are often then treated with a potent cancer drug called enzalutamide. An androgen receptor blocker, enzalutamide stunts tumor growth by keeping male hormones within prostate tumor cells from binding to and activating an androgen receptor protein.  Unfortunately, enzalutamide does not work indefinitely, and tumors eventually become resistant to it as well.

As published in eLife, Dr. Sharifi’s team discovered a complex cascade of events – a “metabolic switch”– that occurs when androgen receptors are blocked with enzalutamide. The drug causes levels of an enzyme called 11βHSD2 to fall, which creates a surplus of the stress hormone cortisol in the tumor cells. This extra cortisol activates its own receptor protein complex, which then takes on the role of the disabled androgen receptor and instructs cancer cells to make more androgens.

Because blocking cortisol from its receptor is not compatible with life, the team searched for other ways to turn off this metabolic switch. Remarkably, they found that restoring levels of 11βHSD2 reversed enzalutamide resistance. While futures studies will need to determine how to increase 11βHSD2 levels safely, this discovery holds great promise for patients who are resistant to all current treatments.

First author on the study was Jianneng Li, PhD, a postdoctoral fellow in Dr. Sharifi’s lab. Dr. Sharifi is a physician-scientist with joint appointments in the Lerner Research Institute, Glickman Urological & Kidney Institute and Taussig Cancer Institute. He holds the Kendrick Family Endowed Chair for Prostate Cancer Research and was recently named a 2016 Harrington Fellow by University Hospitals’ Harrington Discovery Institute. He is co-director of the Lerner Research Institute’s Center of Excellence in Prostate Cancer Research.

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