New target shows promise against drug-resistant prostate cancer

May 26, 2021
Drug resistance is a significant hurdle for prostate cancer, and researchers may have found a way to prevent it. (Shutterstock)

Drug resistance is a significant hurdle for prostate cancer, and researchers may have found a way to prevent it. (Shutterstock)

Researchers have discovered a new target to treat drug-resistant prostate cancer and shown that they can effectively slow tumor growth in mice, potentially opening up new avenues for better treatment of the common and deadly disease.

Common medication for prostate cancer includes androgen-blocking drugs such as enzalutamide, yet prior research has shown that tumors treated by these drugs may switch to cortisol receptors, rather than androgen receptors, to foster their growth. In a study published Wednesday in Science Translational Medicine, Cleveland Clinic researchers successfully blocked the protein that governs cortisol synthesis with rucaparib, a drug approved by the U.S. Food and Drug Administration, combined with enzalutamide.

Prostate cancer will affect about 12.5% of men over the course of their lifetime, according to National Cancer Institute data from 2016-18. And while occurrences have dropped from 234.3 cases in every 100,000 men in 1992 to 106.8 cases for every 100,000 men in 2018, prostate cancer remains the second-leading cause of cancer death for men. According to the American Cancer Society, it will kill one out of 41 men.

Drug resistance presents a significant hurdle not only for prostate cancer, but all cancers and all types of treatment.

This new paper is part of a seven-year project to investigate how tumor cells handle and metabolize different steroid hormones. Earlier research from this team showed that drug-resistant tumors have higher levels of cortisol due to the loss of another enzyme that typically inactivates cortisol. 

"From that time on, we were looking for a way to reverse the process. Is there a way to basically replace the function of that enzyme that's lost?" said senior author Nima Sharifi, director of Cleveland Clinic's Genitourinary Malignancies Research Center. "That's what really inspired this current story." 

Drug-resistant prostate cancer involves the interaction of three different enzymes or proteins. 11β-HSD2 and 11β-HSD1 are essentially the opposites of one another. 11β-HSD2 converts cortisol, a stress hormone, into its inactive form, cortisone. 11β-HSB1, on the other hand, turns cortisone into cortisol, and it needs the protein H6PD to function. Essentially, treatment-resistant tumors deactivate 11β-HSD2, and allow cortisol to accumulate by enriching 11β-HSB1 and H6PD.

When treatment with androgen receptor blockers such as enzalutamide leads to drug resistance, tumor cells seem to activate this response by using the cortisol-regulating proteins. However, the exact mechanism of why tumors eventually resist treatment remains unknown, and is still a major source of inspiration for new research, according to Sharifi. He says that the pathway he and his colleagues have identified is likely a major factor.

The team targeted H6PD because prior research on a genetic syndrome showed that one can reverse the action of 11β-HSD1 by blocking H6PD, a protein that is found at higher levels in drug-resistant tumors, and is required for 11β-HSD1 function. The result of blocking H6PD mimics the role of 11β-HSD2, allowing for normal regulation of cortisol, rather than fostering an abundance of it, as 11β-HSD1 acting alone would do. 

To determine how blocking H6PD may affect tumor growth, Sharifi and his colleagues implanted two mouse models with human prostate cancer cell lines. They treated one of the mice with a combination of enzalutamide and rucaparib, and the other with just enzalutamide. They found that when enzalutamide was combined with rucaparib, tumor growth slowed. 

Sharifi and his team also studied 12 samples of prostate tumor tissue, and found that all of them also contained high levels of H6PD, further confirming the relationship between tumor growth and H6PD. 

Rucaparib is currently used in advanced prostate cancer patients who possess certain genetic mutations, and while it is FDA-approved, it is not approved for use in combination with other drugs. However, according to Sharifi, rucaparib is only a modest blocker of H6PD, and he would be interested in finding stronger H6PD-blocking drugs for potential use. 

Finding these new drugs, however, is difficult, as the protein structure of H6PD "has not been resolved," according to the study, and therefore, "The precise molecular basis for the interaction between drug and enzyme has yet to be determined." Other researchers are currently engineering bacteria to discover the processes that new cancer drugs could target. 

The current research has implications not only for cancer research, but for the role of cortisol in disease overall. 

"There's clearly prostate cancer relevance for drug resistance, but at the same time, the more potential broad application is that cortisol is a stress hormone and is implicated in a variety of physiological processes, and this tells us something very basic and fundamental about the regulation of cortisol and cortisol stimulation of its respective receptor," Sharifi said in an interview with The Academic Times. "I think it has relevance even beyond prostate cancer in terms of anything that's driven by glucocorticoids or stress hormones."

As with many new therapies, the combination treatment of rucaparib and enzalutamide for targeting H6PD will need to undergo clinical trials to determine its effectiveness in a clinical setting. Some of these trials will soon begin, and their data could be available in two to three years, according to Sharifi.

Future research could also include the search for better drugs that can more potently block the pathway that allows tumors to grow using cortisol, according to Sharifi, though this research will likely take longer than the clinical trials. 

The study, "Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation," published May 26 in Science Translational Medicine, was authored by Jianneng Li, Michael Berk, Mohammad Alyamani, Navin Sabharwal, Christopher Goins, Joseph Alvarado, Mehdi Baratchian, Ziqi Zhu, Shaun Stauffer, Eric A. Klein and Nima Sharifi, Cleveland Clinic. 

Saving
We use cookies to improve your experience on our site and to show you relevant advertising.