Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer

The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed a novel class of agents (thailanstatins, TSTs, spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application. This article is protected by copyright. All rights reserved.

International journal of cancer. 2017 Jul 19 [Epub ahead of print]

Bin Wang, U-Ging Lo, Kaijie Wu, Payal Kapur, Xiangyang Liu, Jun Huang, Wei Chen, Elizabeth Hernandez, John Santoyo, Shi-Hong Ma, Rey-Chen Pong, Dalin He, Yi-Qiang Cheng, Jer-Tsong Hsieh

Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas, 76107, USA.

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