Abstract 5249: LuCaP prostate cancer xenografts: Models that allow clinically relevant investigation of prostate cancer in a preclinical setting

Abstract

Abstract PCa is an extremely heterogeneous disease and generating relevant data invariably requires the use of multiple models. A paucity of pre-clinical models that closely replicate the diversity of the disease seen in man, has limited our understanding of PCa biology and evaluation of novel therapeutic strategies. The objective of our studies was to establish and characterize multiple novel PCa xenografts to enable the use of multiple models in preclinical studies leading to the generation of clinically and biologically relevant data. We have established 28 novel PCa xenografts and our characterization studies show that these models portray the characteristics and reflect the diversity of the disease observed in patients. We have established xenografts from primary PCa and PCa metastases from which 24 are adenocarcinomas and 4 are neuroendocrine models. Unsupervised gene expression array clustering analyses revealed (a) association between the xenograft and the originating 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. Furthermore, we have performed extensive characterization of these models that includes: (a) basic histology, (b) serum PSA levels, (c) tumor doubling time, (d) expression of multiple biomarkers by immunohistochemistry (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 and docetaxel. Similar to patient tumor samples, LuCaP xenografts display considerable diversity: they express variable amounts of PSA (range from 0-1000 ng/ml/1 g), different levels of AR and AR splice variants after castration, and significant heterogeneity in all biomarkers evaluated. Heterogeneity was also observed in responses to therapy; prolonged survival (PS) following androgen ablation or docetaxel each ranged from 1 - 7.3 fold. Our characterization also show that 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. In summary these 28 LuCaP PCa xenograft lines are highly diverse and clinically relevant models to study PCa biology and evaluate new treatment modalities. Results generated using a single model can provide misleading information because of heterogeneity of PCa in patients. Therefore use of multiple models and comparison of the results is particularly important, providing superior insight into clinical relevance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5249. doi:1538-7445.AM2012-5249