Abstract 2779: Establishment and molecular characterization of a panel of Asian patient-derived tumor xenograft models .

Abstract

Abstract Rodent tumor models with histological and molecular resemblance of human tumors and improved predictive value for clinical drug response are highly desired for oncology drug discovery and development. Patient-derived xenograft (PDX) tumor models are believed to better preserve features of human malignancy than cancer cell line-derived xenograft models. We have established more than 170 PDX models from Asian-prevalent human tumors in SCID or nude mice. Here we report molecular and pharmacological profiling of a panel of pancreatic adenocarcinoma (PAC) and hepatocellular carcinoma (HCC) models. Among 13 PAC models, Sequenom analysis showed KRAS mutation in all models, p53 mutation in 3, p16/CDKN2A deletion in 9 and SMAD4 deletion in 4 models. Comparison of transcriptomes by Affymetrix U133Plus2 between the original tumor and derived xenografts at different passages (P1-P6) in one PAC model revealed a high degree of similarity (R2 =0.92-0.97). Also, the gene mutational status and histological characters remained unchanged across the parental tumor and different passages of the PDX model. Evaluation of response to Gemzar treatment (60 mpk, Q4D x 3) showed significant tumor regression in 6 PAC models and partial tumor growth inhibition in 4 PAC models. Notably, the regression cohort and the partial response cohort displayed differential gene expression patterns. In addition, primary tumor cells derived from PAC models via tissue digestion were tested in vitro with Gemzar. The in vitro sensitivity to Gemzar of derived cells correlated with in vivo response of the parental PAC models. Gene expression analysis in 11 HCC models found aberrant gene expression involving several signaling pathways such as WNT, EGF/IGF and TGF-β, which recapitulate the alteration of these pathways in human HCC. These HCC PDX models exhibited major features of three HCC subclasses defined by the study in human HCC: S1 with activation of WNT and TGF-β pathways, S2 with enriched AKT and MYC activation and S3 with β-catenin activation. The response of these models to Sorafenib was also examined and varying degrees of sensitivity to Sorafenib were observed. Together, we have successfully generated PDX tumor models that preserve the histological and biological properties of the original human tumor and represent a heterogeneous patient population with varying degree of response to current stand of care. These models are a relevant and powerful tool for evaluation of anticancer therapeutics. Whole genome sequencing and gene expression profiling by RNAseq on PDX models are being preformed. Citation Format: Xiaoran Qin, Zhonghua Tang, Gang Hu, Kedong Ouyang, Ke Wang, Fu Li, Fubo Xie, Qiuming Pan, Min Shi, Gang Zhao, Yixin Zhang, Chunchao Zhu, Danyi Wen, Weikang Tao. Establishment and molecular characterization of a panel of Asian patient-derived tumor xenograft models . [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 2779. doi:10.1158/1538-7445.AM2013-2779