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 post-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 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.

BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1

“…These results further confirm that AR interacts with BMI1, but not RING1B. More importantly, using two CRPC patient-derived xenograft (PDX) models 11 —LuCaP 35CR and 86.2CR—we further confirmed the interactions between AR and BMI1 in prostate cancer patient tissues (Fig. 1g ).…”

“…One of the important mechanisms of enzalutamide resistance is the increased expression of AR variants lacking the ligand-binding domain, the best characterized of which is AR-V7 6 , 7 . Using LuCaP 35CR 11 , an enzalutamide-resistant and abiraterone-resistant CRPC PDX model, we found that combinatorial treatment of PTC209 and enzalutamide significantly improves the clinical outcomes when compared with those utilizing enzalutamide alone (Fig. 6f and Supplementary Fig.…”

Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

“…These experiments identified consistent sensitivity to treatment with CX-5461 plus CX-6258, extending our previous work with these compounds to diverse castration-resistant tumours [11]. More broadly, our approach highlights the utility of different types of patient-derived models, including explants and PDXs, in prostate cancer research [5,34–36].…”

Application of Prostate Cancer Models for Preclinical Study: Advantages and Limitations of Cell Lines, Patient-Derived Xenografts, and Three-Dimensional Culture of Patient-Derived Cells

“…The LuCaP PDX models were established from primary PCa tumors or PCa metastases derived from operative specimens and metastatic CRPC samples obtained by performing tissue acquisition necropsy at the University of Washington [20,128,129,130,131,132,133,134,135,136,137,138,139,140]. During 1991–2005, 261 PCa samples were collected from 156 patients and were implanted subcutaneously into male SCID mice.…”

“…Although abiraterone treatment significantly inhibits the proliferation of LuCaP 136CR-derived tumors, it does not inhibit or only minimally inhibits the proliferation of LuCaP 35CR-derived tumors. The molecular signature of secreted proteins associated with an abiraterone ultra-responsive phenotype has been determined [132]. The CRPC PDX models can be used to evaluate new drugs targeting histone acetyltransferase paralogue p300 and CREB-binding protein [137,138].…”