A new study shows how galeterone is metabolized in the body, suggesting that it shares similarities with other steroidal anti-androgen drugs used to treat advanced prostate cancer. The finding could lay the foundation for development of next-generation drugs that offer better treatment options for the disease.
The study titled, “Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities,” was published in the journal Cell Chemical Biology.
Prostate cancer growth is fueled by male androgens, such as testosterone. Generally, prostate cancer is sensitive to androgen deprivation therapy, also known as medical castration. However, the tumor often becomes resistant to this type of treatment as it starts to synthesize its own stores of testosterone and/or dihydrotestosterone. That has led researchers to develop a new class of anti-androgen drugs that stop the supply of these hormones to the prostate tumor.
“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,” Nima Sharifi, MD, Cleveland Clinic, lead author on the study, said in a press release. “Our goal is to improve the use and role of these existing drugs and hopefully design new therapies that work better and longer.”
Galeterone, a Phase 3 clinical trial candidate for castration-resistant prostate cancer, is an inhibitor of the enzyme Cytochrome P450 17A1 (CYP17A1). The enzyme is involved in catalyzing reactions that lead to the production of androgens. By blocking CYP17A1, galeterone can stop androgen production.
Furthermore, galeterone is also an androgen receptor (AR) antagonist. As an AR antagonist, galeterone stops androgens from binding to their receptors and conducting their normal function. That means galeterone works through a dual mechanism to stop the growth of prostate cancer.
Researchers at the Cleveland Clinic Lerner Research Institute’s Department of Cancer Biology set out to determine how galeterone was metabolized in our bodies. They discovered that galeterone metabolizes into a molecule called D4G (Δ4-galeterone), which inhibits production of androgens, thereby decreasing the amount of androgens available to cancer cells.
The same researchers had previously shown that another anti-androgen drug called Zytiga (abiraterone) is metabolized similarly by being converted to a molecule called D4A (Δ4-abiraterone), which also has anti-tumor activity.
One of the issues is that both D4A and D4G can also be converted, albeit to a small degree, to molecules that stimulate tumor growth rather than impede it. The study authors note that it is necessary to continue to engineer these molecules to increase efficacy.
Taken together, results from the two studies suggest that anti-androgen drugs undergo similar metabolism, which leads to the production of similar molecules that have anti-tumor activity.
“New agents and a clearer understanding of drug mechanisms are both urgently required to improve outcomes for treatment-resistant advanced prostate cancer,” Sharifi said. “This work provides an important foundation that hopefully will lead to better treatment strategies for this disease.”
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