Promising drug target for aggressive prostate cancer

Researchers at Cleveland Clinic, led by Dr Nima Sharifi, have identified a promising drug target for treating and preventing aggressive, drug-resistant prostate cancer. Their findings have been published in the journal Science Translational Medicine.

Enzalutamide, a current standard-of-care hormone therapy for metastatic prostate cancer, works by blocking androgen receptors, which are proteins that help drive cancer cells. While initially effective, most patients eventually develop resistance to the treatment. This resistance occurs when androgen receptors are blocked and cancer cells adapt to get their ‘fuel’ from a similar receptor, called the glucocorticoid receptor. These glucocorticoid receptors bind to and interact with the stress hormone cortisol.

In an earlier study, published in eLife, Dr Sharifi and his team linked enzalutamide resistance to increased tumour cortisol levels. They found that tumours typically express a protein called 11β-HSD2, which inactivates cortisol. However, when this protein expression is inhibited in some tumours, cortisol and the glucocorticoid receptor are stimulated and become available for use by cancer cells.

In their new study, the researchers demonstrated that, in addition to decreased expression of 11β-HSD2, resistant tumours also have increased levels of the protein H6PD. As noted by study co-author Dr Eric Klein, Chair of Cleveland Clinic’s Urology & Kidney Institute, “We found elevated levels of H6PD in both animal models and patient tissues, particularly after treating tumours with enzalutamide.”

Inhibiting H6PD subsequently led to significantly reduced tumour sizes and improved survival among mouse models with drug-resistant prostate cancer. According to Dr Sharifi, who is also the Director of Cleveland Clinic’s Genitourinary Malignancies Research Center, “Our study findings suggest that pharmacologically inhibiting the H6PD protein can reverse drug resistance in prostate cancer cells.

“By blocking this protein, we are able to prevent cancer cells from utilising their backup fuel supply — cortisol and its receptor. When we block this pathway, tumours begin to become responsive to standard treatments again.

“With lower levels of 11β-HSD2, which normally functions to cut off the fuel supply to drug-resistant cancer cells, the cells are free to continue to grow and spread unchecked. By inhibiting the H6PD protein, however, we were able to reinstate anti-cortisol effects. This finding is key to better understanding how disruptions in cortisol metabolism contribute to cancer cells’ growth and spread.”

The researchers targeted H6PD with rucaparib, a drug already approved by the US Food and Drug Administration. Researchers administered enzalutamide to mouse models of aggressive prostate cancer that expressed H6PD and those where the protein was blocked with rucaparib. The models where H6PD was blocked had significantly smaller tumours and longer progression-free survival following enzalutamide treatment.

“These findings represent an exciting new opportunity to potentially reverse drug resistance in advanced prostate cancer,” said Dr Howard R Soule, Executive Vice President and Chief Science Officer of the Prostate Cancer Foundation (PCF). “PCF commends Dr Sharifi and the team on their achievement and proudly supports their work to bring us closer to our mission to eliminate death and suffering from prostate cancer.”

Image credit: ©stock.adobe.com/au/SunnySmile

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