Overexpression of steroid sulfatase (STS) in prostate cancer cells increased androgen synthesis and conferred resistance to enzalutamide. The complementary experimental approach –inhibiting STS– improved enzalutamide efficacy. These studies suggest that STS can drive prostate cancer, and initiate resistance through an alternative synthesis of androgen1.
Prof. Allen C. Gao (University of California Davis, USA) presented the abstract that won the EAU20 Best Abstract Award for Oncology. The hypothesis formed by Prof. Gao’s research team stemmed from the observation that despite anti-androgen therapy, serum steroid levels of precursors for androgen synthesis (dehydroepiandrosterone sulfate and dehydroepiandrosterone) remained high; notably, their catalyzing enzyme STS was also highly overexpressed in castration-resistant prostate cancer (CRPC) patients and resistant cells. The abundance of all precursors together with their catalyzing enzyme STS is strongly suggestive that an alternate mechanism is being implemented to synthesize androgen, which in turn may confer resistance to enzalutamide, abiraterone, apalutamide, and darolutamide.
To test their hypothesis, Prof. Gao’s team fist cataloged the overexpression of STS in CRPC patients and resistant cells. Additional experiments confirmed that STS overexpression stimulates intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone.
Conversely, inhibiting STS expression using RNA silencing technology (siRNA) suppressed in vitro prostate cancer cell growth and androgen receptor (AR) signaling. To test whether the enzymatic catalyzation function of STS was essential for this effect, small-molecule inhibitors (STSi) reducing STS enzymatic activity likewise suppressed AR transcriptional activity, with subsequent effects on the growth of resistant C4-2B and Vertebral-Cancer of the Prostate (VCaP) cells. In VCaP prostate xenograft models, blocking STS enzymatic activity with STSi suppressed resistant VCaP xenograft growth and decreased serum prostate-specific antigen (PSA) levels. Furthermore, STSi enhanced enzalutamide efficacy in vitro and in vivo.
In conclusion, Prof. Gao provided the first experimental evidence that overexpression of STS in CRPC cells has consequent effects on tumor cell proliferation and confers resistance to anti-androgens by alternate androgen synthesis routes. The investigators identified several novel small-molecule STSi agents that are being worked up for additional preclinical testing.
Reference:
1. Gao AC, et al. Inhibition of steroid sulfatase suppresses androgen signaling and improves response to enzalutamide. EAU20 Virtual Congress, 17-26 July 2020, Abstract PT090.