Researchers may have found key to blocking enzalutamide resistance in men with prostate cancer

Liz Meszaros, MDLinx | February 14, 2017

Blocking the metabolic cascade that leads to resistance to enzalutamide—a synthetic non-steroidal antiandrogen currently approved for the treatment of metastatic, castration-resistant prostate cancer—may be a viable approach to restoring its efficacy in killing cancer cells, according to researchers from the Cleveland Clinic, Cleveland, OH. They may have discovered the pathway by which this chain of events is “turned on,” and reported their results online in eLife.

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Blocking resistance

Restoration of 11beta-hydroxysteroid dehydrogenase-2 (11beta-HSD2)—an enzyme—may stop the cascade of events that leads to drug resistance.

Enzalutamide actively blocks the interaction between androgens within the tumor cells and an androgen receptor protein, which is then activated and instructs the tumor cell to proliferate. Thus, this agent renders the tumor’s androgens inactive.

But, there is a much more complex cascade of events that occurs when these androgen receptors are blocked via enzalutamide. In response, levels of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2)—an enzyme—plummet, which creates a surplus of cortisol within the tumor cells. This cortisol activates its own receptor protein complex, which “fills in” for the disabled androgen receptor, instructing the tumor cells to produce more androgens.

Since blocking cortisol from its receptor is neither possible nor desirable, lead author Nima Sharifi, MD, Cleveland Clinic’s Lerner Research Institute Department of Cancer Biology, Glickman Urological & Kidney Institute, and Taussig Cancer Institute, and colleagues sought to find different pathways to the same end, and essentially disrupt the metabolic switch that occurs when androgen receptors are blocked with enzalutamide.

In human prostate cancer tumor cells grown in mice, they found that by restoring levels of 11ßHSD2, and thus circumventing the ensuing production of surplus cortisol by the tumor cell, resistance to enzalutamide was reversed.

“This major discovery demonstrates that tweaking the metabolism induced by cancer drugs can have major benefits to patients in prostate and possibly other cancers,” said Dr. Sharifi.

“We need more studies to determine how to safely increase 11βHSD2 in patients, but we are a step closer to finding answers and hopefully prolonging the lives of men who are in the unfortunate situation of being resistant to all current therapies,” said Dr. Sharifi, who also holds the Kendrick Family Endowed Chair for Prostate Cancer Research and was recently named a 2016 Harrington Fellow by University Hospitals’ Harrington Discovery Institute.

The research was supported by the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289), the Prostate Cancer Foundation, and the American Cancer Society. The funders had no role in the study’s design, data collection and interpretation, or the decision to submit the work for publication.

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