Researchers Discover Similarities in Next-Generation Prostate Cancer Drugs

Cleveland Clinic researchers have shown for the first time how advanced prostate cancer drugs are processed in the body and how their antitumor activity might change depending on how they are metabolized. Their pre-clinical findings, published in Cell Chemical Biology, may lay the foundation for improving therapies for treatment-resistant, aggressive prostate cancer.

These next-generation anti-androgens, including galeterone, abiraterone and enzalutamide, have been shown to improve survival in patients with castration-resistant prostate cancer (CRPC). Unfortunately, tumors eventually become resistant, highlighting the need for new therapies.

“Despite an array of improved treatment options that have become available over the past decade, prostate cancer remains the second leading cause of cancer mortality in men in the United States. There are few therapeutic options for men whose cancer has become resistant to all therapies,” says Cleveland Clinic medical oncologist and prostate cancer researcher Nima Sharifi, MD, lead author on the study. “Our goal is to improve the use and role of these existing drugs and hopefully design new therapies that work better and longer.” Dr. Sharifi holds joint appointments in Cleveland Clinic’s Lerner Research Institute, Glickman Urological & Kidney Institute and Taussig Cancer Institute.

Galeterone metabolites defined

Dr. Sharifi’s team has shown that when galeterone is metabolized, it is converted to the intermediate molecule D4G, which blocks androgen synthesis and reduces the amount of androgens available to cancer cells. A pitfall is that galeterone also converts to another molecule that may stimulate the tumor.

Dr. Sharifi previously found that abiraterone is metabolized in a similar manner. He went on to show in landmark studies that abiraterone’s metabolite D4A has greater antitumor activity than abiraterone alone and that other molecules stimulate tumor growth, suggesting that the drug should be fine-tuned to improve efficacy.

Dr. Sharifi’s new findings suggest that effective steroidal antiandrogens share common metabolic activities and that their metabolites should be closely examined for their effects on tumor survival. The findings may also guide medical decision making in the use of steroidal vs. nonsteroidal drugs for advanced prostate cancer.

Urgent need for better drugs

“New agents and a clearer understanding of drug mechanisms are both urgently required to improve outcomes for treatment-resistant advanced prostate cancer,” says Dr. Sharifi. “This work provides an important foundation that hopefully will lead to better treatment strategies for this disease.”

First authors on the paper are Lerner Research Institute postdoctoral fellow Mohammad Alyamani, PhD, and former fellow Zhenfei Li, PhD, who has started an independent laboratory in Shanghai, China. Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic.

This work has been supported by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award, a Prostate Cancer Foundation Challenge Award, an American Cancer Society Research Scholar Award, grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289), and a grant from the US Army Medical Research and Materiel Command, a Prostate Cancer Foundation Young Investigator Award.