Targeting steroid sulphatase in resistant prostate cancer cells

Overexpression of steroid sulphatase (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 alternative synthesis of androgen [1].

Prof. Allen C. Gao (University of California Davis, USA) presented the abstract that won the EAU20 Best Abstract Award 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 sulphate and dehydroepiandrosterone) remained high; notably, their catalysing enzyme STS was also highly overexpressed in castration-resistant prostate cancer (CRPC) patients and resistant cells. The abundance of all precursors together with their catalysing enzyme STS is strongly suggestive that an alternate mechanism is being implemented to synthesise androgen, which in turn may confer resistance to enzalutamide, abiraterone, apalutamide, and darolutamide.

To test their hypothesis, Prof. Gao’s team fist catalogued 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) signalling. To test whether the enzymatic catalysation 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 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 tumour 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.

1. 
   
   1. Gao AC, et al. EAU20 Virtual Congress, 17-26 July 2020, Abstract

Posted on 20 August, 202018 March, 2021