title: Characterization of an Abiraterone Ultraresponsive Phenotype in Castration-Resistant Prostate Cancer Patient-Derived Xenografts.
abstract: Purpose:To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).Experimental Design:SCID mice bearing LuCaP 136CR, 77CR, 96CR, and 35CR PDXs were treated with AA. Tumor volume and prostate-specific antigen were monitored, and tumors were harvested 7 days after treatment or at end of study for gene expression and immunohistochemical studies.Results:Three phenotypic groups were observed based on AA response. An ultraresponsive phenotype was identified in LuCaP 136CR with significant inhibition of tumor progression and increased survival, intermediate responders LuCaP 77CR and LuCaP 96CR with a modest tumor inhibition and survival benefit, and LuCaP 35CR with minimal tumor inhibition and no survival benefit upon AA treatment. We identified a molecular signature of secreted proteins associated with the AA ultraresponsive phenotype. Upon resistance, AA ultraresponder LuCaP 136CR displayed reduced androgen receptor (AR) signaling and sustainably low nuclear glucocorticoid receptor (nGR) localization, accompanied by steroid metabolism alteration and epithelial-mesenchymal transition phenotype enrichment with increased expression of NF-κB-regulated genes; intermediate and minimal responders maintained sustained AR signaling and increased tumoral nGR localization.Conclusions:We identified a molecular signature of secreted proteins associated with AA ultraresponsiveness and sustained AR/GR signaling upon AA resistance in intermediate or minimal responders. These data will inform development of noninvasive biomarkers predicting AA response and suggest that further inhibition along the AR/GR signaling axis may be effective only in AA-resistant patients who are intermediate or minimal responders. These findings require verification in prospective clinical trials.Clin Cancer Res; 23(9); 2301-12. ©2016 AACR.
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.|State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Lam
authors.affiliation: LabConnect, Seattle, Washington.
authors.forename: Ryan
authors.initials: R
authors.lastname: McMullin
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Nguyen
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Lisha G
authors.initials: LG
authors.lastname: Brown
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Holt
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.affiliation: Janssen Research and Development, Raritan, New Jersey.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Ricci
authors.affiliation: Janssen Research and Development, Beerse, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Verstraeten
authors.affiliation: Janssen Research and Development, Spring House, Pennsylvania.
authors.forename: Shibu
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.|Department of Veterans Affairs Medical Center, Seattle, Washington.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington. ecorey@u.washington.edu.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
mesh_terms: D000069501:Abiraterone Acetate / Q000008:administration & dosage*; D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D000069501:Abiraterone Acetate