Novel drug byproduct inspires potential precision treatments for prostate cancer

Naveed Saleh, MD, MS, for MDLinx | July 26, 2018

Men with advanced prostate cancer and an inherited genetic variant called HSD3B1 experience upregulation of androgens after treatment with abiraterone, an inhibitor of extragonadal androgen synthesis that is a common treatment for prostate cancer, according to a new study published in Endocrinology.

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“We have strong evidence that HSD3B1 status affects abiraterone metabolism and probably its effectiveness,” said lead author Nima Sharifi, MD. “If confirmed, we hope to identify an effective alternative drug that might be more effective in men with this genetic anomaly.”

As demonstrated in metastatic prostate cancer models, abiraterone administration results in the synthesis of a testosterone-like byproduct called 5α-abiraterone, which actually feeds tumor growth and trips lethal pro-cancer pathways.

“We are hopeful these finding[s] will lead to us being able to better tailor prostate cancer treatments based on a patient’s specific genetic make-up,” said lead author Nima Sharifi, MD, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH. “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.”

HSD3B1 codes for 3βHSD1, which has an enzymatic activity that is necessary for the synthesis of potent androgens from adrenal precursor steroids in prostate cancer. The HSD3B1 germ line variant, wrote the authors, “encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation.”

Most experts recognize that intratumoral androgen synthesis, or compensatory androgen synthesis, is upregulated after deprivation of gonadal testosterone, thus mediating the pathogenesis of castration-resistant prostate cancers. Conversely, Dr. Sharifi and colleagues expected that with androgen receptor (AR) stimulation, HSD3B1 transcript and potent androgen synthesis from extragonadal precursor steroids would be suppressed by AR stimulation.

In their tumor cell models, however, the investigators were surprised to observe that HSD3B1 is transcriptionally upregulated in response to androgen treatment, thus yielding an increase in a functional 3βHSD1 protein and heightened conversion from adrenal dehydroepiandrosterone (DHEA) to a potent downstream androgen. Notably, the researchers conceded it is possible “that our data do not accurately reflect the physiologic state in vivo.”

According to the authors, this unexpected finding indicates a “feed-forward regulatory mechanism of AR stimulation” that potentiates the synthesis of AR agonists. The team found that this upregulation occurs regardless of wild-type or variant HSD3B1 status. This regulatory mechanism could sustain a basal level of signaling that drives tumors toward castration-persistent prostate cancer, which invariably follows androgen deprivation therapy, or chemical castration.

Dr. Sharifi and colleagues suggest that worse clinical outcomes in advanced prostate cancer patients with the HSD3B1 variant could be secondary to increased levels of intratumoral androgens enabled by the variant, which they observed in this study, and in turn effect positive feedback and boost HSD3B1 transcription over the top—more than that seen with the wild-type.

This rationale could support efforts “testing the role of AR antagonists in blocking steroidogenesis enabling elevated HSD3B1 transcript”—particularly in patients with the HSD3B1 variant.

The researchers suggest that exploring the impact of abiraterone on clinical outcomes in patients with castration-resistant prostate cancer would be a next step.

“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,” reflected Eric Klein, MD, chair of Cleveland Clinic Glickman Urological and Kidney Institute.

To read more about this study, click here

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