journal contribution
posted on 2023-03-31, 23:46 authored by Adam G. Sowalsky, Ines Figueiredo, Rosina T. Lis, Ilsa Coleman, Bora Gurel, Denisa Bogdan, Wei Yuan, Joshua W. Russo, John R. Bright, Nichelle C. Whitlock, Shana Y. Trostel, Anson T. Ku, Radhika A. Patel, Lawrence D. True, Jonathan Welti, Juan M. Jimenez-Vacas, Daniel Nava Rodrigues, Ruth Riisnaes, Antje Neeb, Cynthia T. Sprenger, Amanda Swain, Scott Wilkinson, Fatima Karzai, William L. Dahut, Steven P. Balk, Eva Corey, Peter S. Nelson, Michael C. Haffner, Stephen R. Plymate, Johann S. de Bono, Adam Sharp Supplementary Figure from Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer
Funding
Prostate Cancer UK (Prostate Cancer)
Prostate Cancer Foundation (PCF)
NIH Intramural Research Program
Congressionally Directed Medical Research Programs (CDMRP)
Wellcome Trust (WT)
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research (BRC)
UK Department of Health
Doris Duke Charitable Foundation (DDCF)
V Foundation for Cancer Research (VFCR)
National Institutes of Health (NIH)
Veterans Affairs Research and Development Service
Lopker Family Foundation
History
ARTICLE ABSTRACT
Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied.
We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome.
In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared with the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy.
This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
