Oncotarget

Research Papers:

Genomic characterization of a large panel of patient-derived hepatocellular carcinoma xenograft tumor models for preclinical development

Qingyang Gu _, Bin Zhang, Hongye Sun, Qiang Xu, Yexiong Tan, Guan Wang, Qin Luo, Weiguo Xu, Shuqun Yang, Jian Li, Jing Fu, Lei Chen, Shengxian Yuan, Guibai Liang, Qunsheng Ji, Shu-Hui Chen, Chi-Chung Chan, Weiping Zhou, Xiaowei Xu, Hongyang Wang and Douglas D. Fang

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Oncotarget. 2015; 6:20160-20176. https://doi.org/10.18632/oncotarget.3969

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Abstract

Qingyang Gu1,*, Bin Zhang1,*, Hongye Sun2, Qiang Xu2, Yexiong Tan3, Guan Wang2, Qin Luo2, Weiguo Xu1, Shuqun Yang1, Jian Li1, Jing Fu3, Lei Chen3, Shengxian Yuan3, Guibai Liang1, Qunsheng Ji1, Shu-Hui Chen1, Chi-Chung Chan1, Weiping Zhou3, Xiaowei Xu4, Hongyang Wang3, Douglas D. Fang1,5

1Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China

2Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China

3Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China

4Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA

5Current address: Cancer Translational Research and In Vivo Pharmacology, China Novartis Institute for Biomedical Research, Zhangjiang Hi-Tech Park, Pudong, Shanghai, 200131 China

*These authors have contributed equally to this work

Correspondence to:

Douglas D. Fang, e-mail: [email protected]

Hongyang Wang, e-mail: [email protected]

Keywords: hepatocellular carcinoma (HCC), patient-derived xenograft (PDX) tumor model, copy number alterations (CNA), single nucleotide polymorphism (SNP), fibroblast growth factor receptor (FGFR)

Received: January 25, 2015     Accepted: May 09, 2015     Published: May 21, 2015

ABSTRACT

Lack of clinically relevant tumor models dramatically hampers development of effective therapies for hepatocellular carcinoma (HCC). Establishment of patient-derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of HCC becomes important. In this study, we first established a cohort of 65 stable PDX models of HCC from corresponding Chinese patients. Then we showed that the histology and gene expression patterns of PDX models were highly consistent between xenografts and case-matched original tumors. Genetic alterations, including mutations and DNA copy number alterations (CNAs), of the xenografts correlated well with the published data of HCC patient specimens. Furthermore, differential responses to sorafenib, the standard-of-care agent, in randomly chosen xenografts were unveiled. Finally, in the models expressing high levels of FGFR1 gene according to the genomic data, FGFR1 inhibitor lenvatinib showed greater efficacy than sorafenib. Taken together, our data indicate that PDX models resemble histopathological and genomic characteristics of clinical HCC tumors, as well as recapitulate the differential responses of HCC patients to the standard-of-care treatment. Overall, this large collection of PDX models becomes a clinically relevant platform for drug screening, biomarker discovery and translational research in preclinical setting.


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