New US research finds common prostate cancer drug could fuel cancer cells in some men

According to new research from the US, a side-effect of a common prostate cancer drug can, in some men with advanced disease who have a specific genetic variant, actually fuel cancer cells.

These findings, published in the Journal of Clinical Investigation, may provide vital information for clinicians to be able to identify those patients who may fare better with a different therapy.

Lead researcher on the study, Dr Numa Sharifi from Cleveland Clinic’s Lerner Research Institute, had previously discovered that in men who have a specific variant in the HSD3B1 gene with an aggressive form of prostate cancer, the treatment outcomes are poorer than in those without the genetic variant. Basically, the HSD3B1 gene — which encodes an enzyme that allows cancer cells to use adrenal androgens for fuel — is overactive in patients with the genetic variant.

Additionally, Sharifi and his team found that men with the genetic anomaly metabolise abiraterone — common drug to treat prostate cancer — differently than men without the variant. This leads to high levels of a testosterone-like byproduct in this specific patient population.

“We are hopeful these finding will lead to us being able to better tailor prostate cancer treatments based on a patient’s specific genetic make-up,” said Sharifi. “More studies are needed, but we have strong evidence that HSD3B1 status affects abiraterone metabolism and probably its effectiveness. If confirmed, we hope to identify an effective alternative drug that might be more effective in men with this genetic anomaly.”

Traditionally, androgen deprivation therapy (ADT) is used in patients with advanced prostate cancer and while this therapy is successful in the early stages of treatment, cancer cells can become resistant and the disease can progress to a lethal phase called castration-resistant prostate cancer (CRPC). At this stage, cancer cells use an alternative source of androgens, produced in the adrenal glands, to grow and spread. Abiraterone is used to block these adrenal androgens.

In this new study, the researchers assessed small molecule byproducts of abiraterone in several groups of men who had progressed to CRPC, finding that patients with the gene variant had high levels of a metabolite called 5α-abiraterone. This metabolite is then responsible for turning on pro-cancer pathways.

“This study adds to our understanding of the deleterious effect of inherited variants of the HSD3B1 gene and holds promise for precision medicine approaches in the management of men with advanced prostate cancer,” added Dr Eric Klein, chair of Cleveland Clinic Glickman Urological and Kidney Institute.

“This study helps to define a novel resistance pathway for abiraterone, a commonly used medication for patients with advanced prostate cancer,” commented Howard Soule, PhD, executive vice president and chief science officer, nonprofit Prostate Cancer Foundation — which supported the study in part with grant money. “Dr Sharifi’s results could enable selection of different systemic therapies for patients who are carriers of certain genetic alterations in the HSD3B1 gene in order to prolong clinical response.”