Abstract 4313: Abiraterone acetate (AA) treatment of prostate cancer patient-derived xenografts (PDX) demonstrates heterogeneity of responses and identifies potential biomarkers of adaptive resistance

Abstract

Abstract AA, a prodrug of the CYP17A1 inhibitor abiraterone, is the first second-line hormonal agent shown to improve survival in metastatic castration-resistant prostate cancer (CRPC); however, as with all available treatments, responding tumors eventually develop resistance. This highlights the importance of identification of mechanisms involved in tumor response and resistance to AA. We evaluated the efficacy of AA in LuCaP CRPC PDXs and investigated mechanisms of response and/or resistance, focusing on androgen receptor (AR) and glucocorticoid receptor (GR) signaling. Mice bearing CRPC LuCaP 35CR, 96CR, 77CR, and 136CR PDXs were treated with AA (0.5 mmol/kg/d), and tumor responses and body weights were monitored. Tumors were harvested 7 days after the beginning of the treatment (d7) and at end of study (EOS) (sacrifice when tumor > 1000 mg). Gene expression analyses using Affymetrix HG-U219 gene array and qPCR were performed to evaluate the validity of established biomarkers and identify novel biomarkers related to AA response. Linear regression model analyses showed that AA inhibited tumor progression in 3 of 4 LuCaP PDXs (96CR, 77CR, 136CR), but the initial response was followed by development of resistance. Corresponding analyses of serum prostate-specific antigen (PSA) levels demonstrated a decrease post AA (96CR: p = 0.051; 77CR: p = 0.001; 136CR: undetectable at baseline). AA improved median survival (77CR: 7 vs 9.5 weeks, p = 0.022; and 136CR: 6.8 vs 21.6 weeks, p < 0.0001), and highly variable responses were observed for 96CR (5.75 vs 10 weeks, p = 0.25). 35CR did not exhibit significant growth inhibition, reduction in PSA, or decreased median survival on AA. Evaluation of gene signatures revealed a negative association of proliferation-associated genes with AA at d7 for 35CR and 136CR, while at EOS these signatures were negatively associated with AA for 96CR and 136CR. Signatures of AR-regulated genes were negatively associated with AA at d7 for 35CR and 136CR, while at EOS they were negatively associated with AA for 96CR and 136CR. Targeted sequencing of the AR ligand binding domain coding sequence did not detect any mutations in any PDX at EOS. Trends toward increased expression of full length AR (ARFL) and splice variant ARv7 were associated with AA at d7 for 136CR. At EOS, trends toward increased ARFL and ARv7 expression were associated with AA for 35CR and 96CR. Significantly increased GR expression was associated with AA at EOS for 96CR and 77CR, and a trend was observed for 136CR. Our results demonstrate model-specific heterogeneity of physiological and molecular responses to AA in CRPC. However, our data indicate that increased ARFL, ARv7, and/or GR could be biomarkers of adaptive resistance and potentially play functional roles in conferring resistance. Citation Format: Hung-Ming Lam, Ryan McMullin, Holly M. Nguyen, Michael Gormley, Roman Gulati, Weimin Li, Deborah Ricci, Karin Verstraeten, Shibu Thomas, Elahe A. Mostaghel, Peter S. Nelson, Robert L. Vessella, Eva Corey. Abiraterone acetate (AA) treatment of prostate cancer patient-derived xenografts (PDX) demonstrates heterogeneity of responses and identifies potential biomarkers of adaptive resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4313. doi:10.1158/1538-7445.AM2015-4313