Characterization of an Abiraterone Ultraresponsive Phenotype in Castration-Resistant Prostate Cancer Patient-Derived Xenografts.

摘要: 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, 35CR PDXs were treated AA. Tumor volume prostate-specific antigen monitored, tumors harvested 7 days after treatment or at end of study for gene expression immunohistochemical studies.Results: Three phenotypic groups observed based on response. An ultraresponsive phenotype was identified 136CR significant inhibition tumor progression increased survival, intermediate responders 77CR 96CR a modest survival benefit, minimal no benefit upon treatment. We secreted proteins phenotype. Upon resistance, ultraresponder displayed reduced androgen receptor (AR) signaling sustainably low nuclear glucocorticoid (nGR) localization, accompanied by steroid metabolism alteration epithelial-mesenchymal transition enrichment NF-κB-regulated genes; maintained sustained AR tumoral nGR localization.Conclusions: ultraresponsiveness AR/GR responders. These data will inform development noninvasive biomarkers predicting suggest that further along axis may be effective only AA-resistant patients who are findings require verification prospective clinical trials. Clin Cancer Res; 23(9); 2301-12. ©2016 AACR.