0 items found

The content in the Resource Centre is not accredited.

PT090: Inhibition steroid sulfatase suppresses androgen signaling and improves response to enzalutamide

Speaker
Prof. A. (Allen) Gao
Authors
Gao A.1, Armstrong M1, Liu C.1, Liu L.2, Yang J.1, Lou W.1, Li P.3, Evans C.1
Institutions
1University of California Davis, Dept. of Urology, Sacramento, United States of America, 2Sichuan University, Dept. of Urology, Chengdu, China, 3Ohio State University, Pharmacy, Columbus, United States of America
Event
35th Annual EAU Congress - Virtual (EAU20V)
Date – time - Location
18 July 2020, 19:40 - 20:10, Virtual room 1
Session
Poster Session - Best abstract session: Oncology
Topic
Prostate Cancer, metastatic - Basic Research & Trials, Novel therapies

Introduction & Objectives

Steroid sulfatase (STS) is a key enzyme that catalyzes the hydrolysis of DHEAS to the biologically active DHEA, which is further metabolized to active androgens that bind the androgen receptor (AR) leading to cell proliferation. DHEAS is the most abundant steroid in blood circulation and significant concentrations of DHEAS are still exist in prostate cancer patients even after treated with ketoconazole or abiraterone, suggesting that this could act as a depot for further downstream androgen production. Currently the role of STS in AR signaling and CRPC is largely unknown. This study determines the role of STS in AR signaling and explores the potential of targeting STS to overcome castration resistance in prostate cancer.

Materials & Methods

Quantitative rt-PCR and Western blotting were used to detect expression levels of STS and AR. Expression of STS was downregulated using siRNA specific to STS. Stable cell lines overexpressing STS were generated and characterized. RNA-seq was performed on the stable clones to determine alterations in gene expression instigated by STS expression. The steroid profiles of the cells were analyzed by LC-MS using the Thermo Scientific Vanquish UPLC/AB Sciex Qtrap system. STS activity was determined by 4-Methylumbelliferyl sulfate assay. Eleven potent STS inhibitors were synthesized and characterized. Prostate cancer cell sensitivity to STS inhibitors was tested using cell growth assays and clonogenic assays. Efficacy of two novel STS inhibitors was tested in vivo in castration relapsed VCaP xenograft tumor models.

Results

STS is overexpressed in CRPC patients and resistant prostate cancer cells including VCaP and C4-2B MDVR. Stable STS overexpression in C4-2B and LNCaP cells increases the levels of testosterone and DHT, respectively. This resulted in increased cell growth and PSA expression in vitro. Inhibiting STS with siRNA suppresses cell growth and AR signaling. Furthermore, STS overexpression in C4-2B and LNCaP cells promoted resistance to enzalutamide and this could be reversed by STS siRNA.  We synthesized and analyzed 11 potential novel STS inhibitors (SI). We identified SI-1 and SI-2 as the most potent inhibitors of STS activity and growth of VCaP cells. They significantly suppressed AR transcriptional activity, suggesting that inhibition of STS activity by SI downregulates AR signaling. SI-1 and SI-2 significantly suppressed the growth of relapsed VCaP cells and tumors and improved enzalutamide treatment in vitro and in vivo.

Conclusions

Overexpression of STS increases intracrine androgen synthesis and confers resistance to enzalutamide in castration resistance prostate cancer cells,  inhibition of this enzyme improves enzalutamide treatment.