Abstract 3242: The molecular and biological characterization of 25 unique prostate cancer xenograft lines, including response to therapy
Authors: Nguyen Holly M. , Corey Eva , Higano Celestia , Lange Paul , Morrissey Colm , Nelson Peter , Plymate Stephen , Roudier Martine , Trask Barbara , True Lawrence , Zhang Xiaotun , Vessella Robert 
Published: February 2011

Introduction: Prostate cancers (PCa) exhibit a wide range of molecular and biological profiles. In concert with this heterogeneity, there is a wide spectrum of responses to therapy. One of the significant limitations in unraveling the complexities of PCa and designing/evaluating novel therapeutic strategies has been the lack of pre-clinical models that closely replicate the diversity seen in man. To overcome this limitation we have developed 25 unique PCa xenograft lines (LuCaP series) where the initiating implants were derived from primary tumors, soft-tissue metastases and bone metastases. This presentation will provide details of a comprehensive molecular and biological characterization of these lines, including their responses to therapy.

Methods: Tumors were obtained either from radical prostatectomies or from our rapid autopsy program, which is designed specifically for the acquisition of metastatic foci. Tumor pieces were implanted into male, immune compromised mice. Characterization involves: (a) quantification of serum PSA levels, (b) basic histology, (c) tumor doubling time, (d) a panel of &gt;15 biomarkers assessed by immunohistochemistry, (e) gene expression array profiles, (f) chromosomal losses and gains, (g) expression of the TMPRSS2:ERG fusion gene, (h) presence of the androgen receptor (AR) and its splice variants, (i) bone remodeling perturbations associated with tumor growth in bone, and (j) response to therapy, including androgen ablation and docetaxel.

Results: Overall, 18% of the attempts to establish xenografts were successful resulting in 25 lines. As in the clinical scenario, these xenografts display a wide range of characterization profiles. While most are adenocarcinomas, 3 are neuroendocrine and all histologically resemble the originating clinical specimen. PSA serum levels can reach into the low thousands of ng/ml for a 1 g tumor. AR gene and protein expression is highly variable and &gt;50% of the lines express a constitutively active AR splice variant. The gene expression profiles show multiple clustering patterns that include a close association of the xenograft with the clinical specimen, pairing of androgen dependent lines with their castrate-resistant offspring and a distinction between adenocarcinoma and neuroendocrine histologies. Five of the lines are PTEN negative and 9 express the TMPRSS2:ERG gene fusion. The bone remodeling response ranges from osteoblastic to lytic. Responses to androgen ablation and docetaxel range from long duration to no response.

Conclusions: These 25 LuCaP PCa xenograft lines provide a highly diverse, yet clinically relevant, panel for the study of PCa biology. This diversity 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 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3242.