Abstract
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 NH 2 -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.
Original language | English (US) |
---|---|
Pages (from-to) | 231-241 |
Number of pages | 11 |
Journal | Prostate Cancer and Prostatic Diseases |
Volume | 19 |
Issue number | 3 |
DOIs | |
State | Published - Sep 1 2016 |
Bibliographical note
Funding Information:ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973. AJA has received funding from a Prostate Cancer Foundation and Movember Global Treatment Sciences Challenge Award. SMD is currently funded by a Movember/Prostate Cancer Foundation Challenge Award, American Cancer Society Research Scholar Grant RSG-12-031-01-TBE, NIH grant R01 CA174777, US Department of Defense Prostate Cancer Research Program grants W81XWH-12-2-0093, W81XWH-13-1-0518, W81XWH-15-1-0633, and W81XWH-15-1-0501, and a grant from the Minnesota Partnership for Biotechnology and Medical Genomics. JL is currently funded by a Prostate Cancer Foundation grant, NIH grant R01 CA185297, and US Department of Defense Prostate Cancer Research Program grants W81XWH-13-2-0093 and W81XWH-15-2-0050.