Enzyme inhibition shows promise for overcoming castration resistance in prostate cancer

Allen Gao, MD, PhD

Inhibition of steroid sulfatase (STS) may be a viable strategy for treating patients with castrate-resistant prostate cancer (CRPC) and improving their response to enzalutamide (Xtandi), according to preclinical research presented by Allen Gao, MD, PhD, during the 2020 European Association of Urology Virtual Congress.

He reported on a series of studies that showed STS increases intracrine androgen production in CRPC cells, promotes CRPC progression, and confers resistance to enzalutamide and abiraterone acetate (Zytiga), whereas inhibition of the enzyme suppresses cancer cell growth and improves enzalutamide treatment.

Gao who is a professor of urology at the UC Davis School of Medicine in Sacramento, California, described the rationale for using STS inhibition as a treatment to for patients with advanced prostate cancer.

“Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in male circulation and can be transported into prostate cancer cells where it can be converted into DHEA by STS,” explained Gao. “Then, DHEA is further processed into the more biologically active compounds, testosterone and dihydrotestosterone.”

"Significant circulating concentrations of DHEAS still exist in patients with prostate cancer being treated with abiraterone,” Gao continued. “The circulating DHEAS, which is present at a level 4000 times higher than the castrate level of circulating testosterone, can serve as a depot for intracrine androgen synthesis.”

As a first step to exploring STS inhibition as a therapeutic strategy, Gao and colleagues undertook studies to confirm that STS was expressed in CRPC cells. In 2 separate experiments, they found STS was overexpressed in metastatic prostate cancer cells compared to benign prostate and primary tumor cells.

Next they showed that STS expression was involved in prostate cancer growth. Using C4-2B cells, Gao and colleagues demonstrated that downregulation of STS expression using STS-specific siRNA reduced cell growth and androgen signaling.

Studying the relationship between STS and intracrine androgen synthesis, the investigators found that when supplemented with DHEAS, cells overexpressing STS produced increased intracellular testosterone compared with controls. Cells overexpressing STS also demonstrated increased resistance to enzalutamide.

Moving forward, the researchers explored STS as a therapeutic target by synthesizing a family of 11 potential STS inhibitors. Initial testing of the novel compounds showed a correlation between their STS inhibitory activity and effect on reducing growth of VCaP cells. The 2 most potent STS inhibitors were selected for use in an in vivo vehicle-controlled study performed in a castration-relapsed VCaP xenograft tumor mouse model. Both STS inhibitors significantly suppressed tumor growth.

In a second experiment performed in the same mouse model, animals were treated with vehicle, enzalutamide, 1 of the STS inhibitors, or enzalutamide plus the STS inhibitor. Treatment effects were determined based on assays of tumor size and proliferation, and the results showed that for both outcomes, the best results were achieved with the combination regimen.

Gao noted that extensive toxicity testing of the STS inhibitor candidates has not yet been done; however, no signals emerged based on limited preliminary observations in the mice.

The live virtual session was moderated by Peter Albers, MD, professor and chairman, department of urology, Heinrich-Heine University, Dusseldorf, Germany. Albers described the work as a breakthrough study in prostate cancer research.

Peter Albers, MD

“The results are very interesting and may alter treatment for metastatic prostate cancer,” he said. “We hope you can continue this work as it is important for understanding endocrine resistance to prostate cancer and may be useful as new drugs emerge.”

The research was awarded first prize in the Oncology Best Abstract Session at the meeting.

Gao is co-inventor of a patent application of selected small molecule inhibitors of STS.

Reference

Gao A. Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract PT090.

<<<More from the 2020 EAU Annual Congress