Nima Sharifi, MD, director of Cleveland Clinic’s Genitourinary Malignancies Research Center speaks about Cleveland Clinic Researchers Identify New Drug Target for Treating Aggressive Prostate Cancer.
Link to Article:
https://newsroom.clevelandclinic.org/2021/05/26/cleveland-clinic-researchers-identify-new-drug-target-for-treating-aggressive-prostate-cancer/
Cleveland Clinic researchers have found a viable therapeutic target for treating and preventing aggressive, treatment-resistant prostate cancer, according to new data published in Science Translational Medicine.
The researchers showed that blocking the protein H6PD decreased tumor growth and enhanced longevity in mice models with drug-resistant prostate cancer, lead by Nima Sharifi, M.D. of Cleveland Clinic’s Lerner Research Institute. H6PD levels were similarly enhanced in biopsied patient tumors, indicating that the protein may be used to treat patients.
Enzalutamide, current standard-of-care hormone treatment for metastatic prostate cancer, operates by inhibiting androgen receptors, proteins that enable cancer cells to grow and spread. While the medication is initially successful, most patients eventually acquire resistance to it. When androgen receptors are inhibited, cancer cells adapt to acquire their “fuel” from the glucocorticoid receptor, which is identical to androgen receptors.
The stress hormone cortisol binds to and interacts with these glucocorticoid receptors. Dr. Sharifi and his colleagues previously linked enzalutamide resistance to elevated tumor cortisol levels in an eLife research. They discovered that cancers commonly produce 11-HSD2, a protein that inactivates cortisol. Cortisol and the glucocorticoid receptor are increased and accessible for use by cancer cells when this protein expression is suppressed in certain cancers.
The researchers found that, in addition to lower expression of 11-HSD2, resistant tumors exhibited higher H6PD levels in this recent investigation.
The researchers used rucaparib, a medication that has previously been licensed by the US Food and Drug Administration, to target H6PD. Dr. Sharifi worked with scientists at Cleveland Clinic’s Center for Therapeutics Discovery to figure out which components of rucaparib are required for the protein to be inhibited chemically.
Researchers gave enzalutamide to mice with aggressive prostate cancer that expressed H6PD and were given rucaparib to inhibit the protein. Following enzalutamide therapy, tumors in H6PD-deficient mice were much smaller and progression-free survival was much prolonged.
The study’s primary author is Jianneng Li, Ph.D., a post-doctoral fellow in Dr. Sharifi’s group who was funded by the National Cancer Institute and the Prostate Cancer Foundation.