Abstract 1583: The biological and molecular characterization of 24 unique prostate cancer xenograft lines, including responses to therapy

Abstract

Abstract Introduction: Prostate cancers (PCa) are heterogeneous which results in an unpredictable and wide range in response to therapy. A significant limitation in unraveling the complexities of PCa and designing/evaluating novel therapeutic strategies is the lack of pre-clinical models that closely replicate the diversity of the disease seen in man. To overcome this limitation we established 24 PCa xenograft lines (LuCaP series). Last year we reported on a subset of these lines. This presentation will provide a detailed biological and molecular characterization of nearly all of these xenograft lines including their responses to therapy. Methods: Xenografts were initiated from tumors acquired at radical prostatectomy or rapid autopsy (enabling acquisition of metastatic foci) and implanted into male immune-compromised mice. Characterization includes: (a) basic histology, (b) serum PSA levels, (c) tumor doubling time, (d) expression of 38 biomarkers by immunohistochemistry (IHC), (e) gene expression array profiles, (f) expression of the androgen receptor (AR) and its splice variants, (g) bone remodeling perturbations associated with tumor growth in bone, and (h) response to therapy, i.e. androgen ablation, docetaxel and anti-IGF-1R. Results: As in the clinical scenario, these xenografts display considerable diversity. All histologically resemble the originating clinical specimen; 20 are adenocarcinomas and 4 are neuroendocrine. Unsupervised clustering revealed (a) association between the xenograft and the originating clinical specimen, (b) pairing of androgen dependent lines with their castrate-resistant offspring, (c) a distinction between adenocarcinoma and neuroendocrine phenotypes and (d) continuous passage in vivo for 2-8 years did not impact gene expression profiles. PSA serum levels range from zero to the low thousands of ng/ml for a 1 g tumor. AR expression is highly variable and >50% of the lines express an AR splice variant after castration. IHC revealed considerable heterogeneity in biomarker expression. In most cases protein expression correlated well with gene expression. The bone remodeling response indicates at least 8 are osteoblastic. Prolonged survival (PS) to therapy was extremely variable; androgen ablation ranged from 1-7.3 fold and docetaxel also from 1-7.3. Interestingly, LuCaP 86.2 expressing predominantly ARv567es was among the least responsive to androgen ablation (PS 1.1) whereas it is one of the most responsive to docetaxel (PS >4). Conclusions: These 24 LuCaP PCa xenograft lines are highly diverse and clinically relevant models for the study of PCa biology. This diversity of phenotypes and responses to therapy most importantly suggests that misleading conclusions can be drawn from use of only one or two PCa models. This is extremely important in the evaluation of new therapeutic strategies, especially those that target specific pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1583. doi:10.1158/1538-7445.AM2011-1583