Prostate cancer (PCa) is a heterogeneous disease, which results in an unpredictable and varied response to therapy. A limitation in unraveling the complexities of PCa and developing / evaluating novel therapeutic strategies has been the lack of pre-clinical models that closely replicate this heterogeneity. To overcome this limitation we have established over 3 dozen PCa xenograft lines (LuCaP series).
Characterization of the xenograft lines derived from PCa primaries and metastases includes: (a) growth properties, (b) expression of 45 biomarkers by immunohistochemistry (IHC), (c) gene expression, (d) copy number gains and losses, (e) expression of the androgen receptor (AR) and its splice variants, (f) bone response (i.e. osteoblastic, osteolytic or mixed), and (g) response to therapy, i.e. androgen ablation, docetaxel and anti-IGF-1R.
Forty distinct xenograft lines comprise the current LuCaP panel. Four are neuroendocine, 12 are castration resistant (CR) sublines and 7 are abiraterone or MDV-3100 resistant sublines. Comprehensive characterization studies have been done on 24 lines. 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 CR sublines, (c) a distinction between adenocarcinoma and neuroendocrine phenotypes and (d) insignificant drift over a 2-5 year period of serial passage. Biomarker expression is quite heterogeneous and in most cases, protein expression correlated well with gene expression.
Importantly, 7 LuCaP models elicit an osteoblastic reaction in the bone, 5 models are PTEN negative, and 8 lines have the TMPRSS2:ERG fusion. The xenograft lines express different levels of AR with some expressing AR splice variants.
Heterogeneity was also observed in responses to therapy; prolonged survival (PS) following androgen ablation or docetaxel treatment ranged from 1 - 7 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 as individual agents and in combination; heterogeneous responses are being observed. To explore mechanisms of resistance, we are also maintaining sublines that developed resistance to abiraterone and MDV-3100.
Conclusions: These LuCaP PCa xenograft lines are highly diverse and clinically relevant models to study PCa biology and to 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 models in preclinical evaluations.
Citation Format: Holly Nguyen, Eva Corey, Colm Morrissey, Peter Nelson, Xiaotun Zhang, Martine Roudier, Stephen Plymate, Lawrence True, Celestia Higano, Robert Montgomery, Paul Lange, Robert Vessella. The biological and molecular characterization of clinically relevant prostate cancer xenograft lines (LuCaP series), including responses to therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 305. doi:10.1158/1538-7445.AM2013-305