Abstract Introduction: Prostate cancer (PCa) is a heterogeneous disease which results in an unpredictable and wide range of responses to therapy. A significant limitation in unraveling the complexities of PCa and developing / 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 have established over 2 dozen PCa xenograft lines (LuCaP series). This poster will provide a summary of the biological and molecular characterization of nearly all of these xenograft lines including their responses to therapy. Methods: Characterization of the xenograft lines derived from primary PCa and PCa metastases includes: (a) basic histology, (b) serum PSA levels, (c) tumor doubling time, (d) expression of 38 biomarkers by immunohistology (IHC), (e) oligo array profiles, (f) expression of the androgen receptor (AR) and its splice variants, (g) bone response, and (h) response to therapy, i.e. androgen ablation, docetaxel and anti-IGF-1R. Results: Of the 28 derived LuCaP xenograft lines, 24 are adenocarcinoma and 4 are neuroendocrine. Our results show that all lines histologically resemble the originating clinical specimen. Unsupervised gene expression array clustering analyses revealed (a) association between the xenograft and the originating clinical specimen, (b) pairing of androgen-sensitive lines with their castration-resistant offspring, (c) a distinction between adenocarcinoma and neuroendocrine phenotypes and (d) that gene expression profiles were not significantly altered by continuous passage in vivo for 2-8 years. Importantly, seven of our models elicit an osteoblastic reaction in the bone, five models are PTEN negative, eight lines have the TMPRSS2:ERG fusion, and there are eight matched pairs of androgen-sensitive and castration-resistant xenografts. As in the clinical scenario, the xenograft lines display considerable diversity. They express variable amounts of PSA (range from 0-1000 ng/ml/1 g), different levels of AR and express an AR splice variant after castration. IHC revealed considerable heterogeneity in all biomarkers evaluated. In most cases protein expression correlated well with gene expression. Heterogeneity was also observed in responses to therapy; prolonged survival (PS) following androgen ablation or docetaxel each ranged from 1 - 7.3 fold. 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). Several novel anti-androgen therapies are currently under investigation. Conclusions: These 28 LuCaP PCa xenograft lines are highly diverse and clinically relevant models to study PCa biology and evaluate new treatment modalities. The diversity of phenotypes and responses to therapy most importantly suggests that misleading conclusions can be drawn from the use of only one or two PCa models in preclinical evaluations. Use of multiple models is extremely important in the evaluation of new therapeutic strategies, especially those targeting specific pathways. Citation Format: Holly Nguyen, Martine Roudier, Lawrence True, Robert Vessella, Eva Corey, Colm Morrissey, Peter Nelson, Xiaotun Zhang, Stephen Plymate, Celestia Higano, Paul Lange. The biological and molecular characterization of 28 unique prostate cancer xenograft lines (LuCaP series), including responses to therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C34.
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Dec 18, 2013
Simon Mcgurk 
Open Access