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Researchers Identify New Drug Target for Treating Aggressive Prostate Cancer

Dr. Sharifi demonstrates that pharmacologically inhibiting the H6PD protein can reverse drug resistance in human-derived preclinical models of enzalutamide-resistant prostate cancer.

05/26/2021



According to new findings published in Science Translational Medicine, researchers in Lerner Research Institute’s Department of Cancer Biology have identified a promising drug target for treating and preventing drug-resistant prostate cancer.

The team, led by Nima Sharifi, MD, reports that inhibiting the protein H6PD significantly reduced tumor sizes and improved progression-free survival among human-derived preclinical models of drug-resistant prostate cancer. They found that H6PD levels were significantly enriched in biopsied patient tumors, as well, suggesting it can be targeted in patients.

Inhibiting H6PD restores important enzymatic activity

New treatment approaches for prostate cancer are desperately needed. Enzalutamide, a current standard-of-care hormone therapy, works by blocking specific receptors that play an important role in fueling cancer cells (called androgen receptors). While enzalutamide is effective early on, most patients eventually develop treatment resistance. This happens because when androgen receptors are blocked, cancer cells learn to rely on a similar receptor, called the glucocorticoid receptor.

In an earlier study published in eLife in 2017, Dr. Sharifi and his team found that enzalutamide resistance can be traced to increased levels of the stress hormone cortisol (a type of glucocorticoid). Tumors typically express a protein called 11β-HSD2, which inactivates cortisol. Resistance occurs, however, when 11β-HSD2 expression is inhibited, which ultimately stimulates the glucocorticoid receptor—enabling cancer cells to efficiently utilize their backup fuel supply.

Here, the researchers demonstrated that, in addition to decreased expression of 11β-HSD2, resistant tumors also have increased expression of H6PD.

“With lower levels of 11β-HSD2, which normally functions to cut off the fuel supply to drug-resistant cancer cells, they are free to continue to grow and spread unchecked,” said Dr. Sharifi, director of Cleveland Clinic’s Genitourinary Malignancies Research Center. “By inhibiting H6PD, however, we were able to reinstate anti-cortisol effects.”

Dr. Sharifi’s close clinical collaborator Eric Klein, MD, chair of Cleveland Clinic’s Urology & Kidney Institute and a co-author on the study, expanded, “Not only did Nima’s team find elevated levels of H6PD among preclinical disease models, but we also observed the same in the clinic when we studied patient tissues. Compared with pre-treatment tumors, H6PD levels were significantly increased following enzalutamide treatment.”

In vivo effects of targeting H6PD

The researchers targeted H6PD with a drug already approved by the U.S. Food and Drug Administration (called rucaparib). Dr. Sharifi worked closely with researchers from Cleveland Clinic’s Center for Therapeutics Discovery to identify what parts of rucaparib are chemically necessary to inhibit the protein.

With this understanding, researchers administered enzalutamide to human-derived preclinical models of drug-resistant prostate cancer that expressed H6PD and those where H6PD was genetically knocked out or inhibited using rucaparib. Compared to the models that expressed H6PD, the H6PD-deficient models exhibited significantly smaller tumors and longer progression-free survival following enzalutamide treatment.

“Taken together, our study findings suggest that inhibiting H6PD resensitizes drug-resistant prostate cancer cells,” said Dr. Sharifi. “By blocking H6PD, we are able to prevent cancer cells from utilizing their backup fuel supply—the glucocorticoid receptor. When we block their primary fuel source, then, they are left without any means to continue to grow and spread.”

He went on to explain that while the team relied on recuparib to block H6PD expression, it was not designed and approved for that purpose—the inhibitory result is considered an off-target effect.

Jianneng Li, PhD, a postdoctoral fellow in Dr. Sharifi’s lab, is first author on the study, which was supported by the National Cancer Institute (part of the National Institutes of Health) and the Prostate Cancer Foundation.




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