Journal
PROSTATE CANCER AND PROSTATIC DISEASES
Volume 19, Issue 3, Pages 231-241Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/pcan.2016.17
Keywords
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Categories
Funding
- Prostate Cancer Foundation
- Patrick C. Walsh Fund
- NIH [R01 CA185297, P30 CA006973, R01 CA174777]
- Movember Global Treatment Sciences Challenge Award
- Movember/Prostate Cancer Foundation Challenge Award
- American Cancer Society Research Scholar Grant [RSG-12-031-01-TBE]
- US Department of Defense Prostate Cancer Research Program [W81XWH-12-2-0093, W81XWH-13-1-0518, W81XWH-15-1-0633, W81XWH-15-1-0501, W81XWH-13-2-0093, W81XWH-15-2-0050]
- Minnesota Partnership for Biotechnology and Medical Genomics
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While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.
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