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 .
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.
- Gao AC, et al. EAU20 Virtual Congress, 17-26 July 2020, Abstract
« Good tolerance of post-RP radiotherapy ± short-term ADT Next Article
Large patient-driven survey reveals QoL issues after prostate cancer treatment »
Table of Contents: EAU 2020
Letter from the Editor
EAU 2020 Highlights Podcast
Surgical Techniques and Safety
The new adjustable artificial sphincter victo: Surgical technique and results after a follow-up of more than one year
New urosepsis data from the SERPENS study
Intra-operative cone-beam computed tomography for detecting residual stones in percutaneous nephrolithotomy
Pressure and temperature: do high-power lasers pose a threat?
Radiation stewardship for patient and endourologist
New lithotripter data: improved stone clearance
Beyond the limits of ultrasound: Three dimensional augmented reality robot assisted partial nephrectomy (3D AR-RAPN) for complex renal masses
Imaging guided surgery with augmented reality for robotic partial nephrectomy
KEYNOTE-426: no QoL differences pembrolizumab + axitinib versus sunitinib
Debate: upfront cytoreductive nephrectomy or not?
Robotic-assisted partial nephrectomy: lower morbidity
Reduced BCG frequency, faster NMIBC recurrence
Nadofaragene firadenovec effective in BCG-unresponsive papillary NMIBC
Understanding MIBC biology for novel treatment options
Prostate Cancer & Imaging
Transperineal laser ablation of prostate
Prostatectomy: R-LRPE better than LRPE for continence
PSMA PET-CT staging is 27% more accurate
Docetaxel + hormonal therapy: improved prostate cancer PFS
ARAMIS subgroup analysis: darolutamide benefits across PSADT groups
Large patient-driven survey reveals QoL issues after prostate cancer treatment
Targeting steroid sulphatase in resistant prostate cancer cells
Good tolerance of post-RP radiotherapy ± short-term ADT
BPH & LUTS
Minimizing post-operative stress urinary incontinence after HoLEP: Our preliminary experience and short-term results of ‘’En Bloc’’ technique with early apical release
LUTS 2-year outcomes: aquablation versus TURP
HoLEP versus PVP in prospective randomised trial
LUTS in the neuro-urologic patient
Testis Cancer & Andrology
Peyronie’s disease: surgical options
Infertility and testis cancer risk: causal or association?
32% more men complain of reduced sex drive in 2019 versus 2009