1. Academic Validation
  2. Patient-Derived Xenograft Models for Intrahepatic Cholangiocarcinoma and Their Application in Guiding Personalized Medicine

Patient-Derived Xenograft Models for Intrahepatic Cholangiocarcinoma and Their Application in Guiding Personalized Medicine

  • Front Oncol. 2021 Jul 13;11:704042. doi: 10.3389/fonc.2021.704042.
Yang Gao 1 Rong Zhou 2 Jun-Feng Huang 3 Bo Hu 1 Jian-Wen Cheng 1 Xiao-Wu Huang 1 Peng-Xiang Wang 1 Hai-Xiang Peng 4 5 Wei Guo 6 Jian Zhou 1 7 Jia Fan 1 7 Xin-Rong Yang 1
Affiliations

Affiliations

  • 1 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
  • 2 Department of Blood Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Intensive Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Shanghai Dunwill Medical Technology Co., Ltd., Shanghai, China.
  • 5 Shanghai Epione Medlab Co., Ltd., Shanghai, China.
  • 6 Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 7 Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) remains one of the most intractable malignancies. The development of effective drug treatments for ICC is seriously hampered by the lack of reliable tumor models. At present, patient derived xenograft (PDX) models prove to accurately reflect the genetic and biological diversity required to decipher tumor biology and therapeutic vulnerabilities. This study was designed to investigate the establishment and potential application of PDX models for guiding personalized medicine and identifying potential biomarker for lenvatinib resistance.

Methods: We generated PDX models from 89 patients with ICC and compared the morphological and molecular similarities of parental tumors and passaged PDXs. The clinicopathologic features affecting PDX engraftment and the prognostic significance of PDX engraftment were analyzed. Drug treatment responses were analyzed in IMF-138, IMF-114 PDX models and corresponding patients. Finally, lenvatinib treatment response was examined in PDX models and potential drug resistance mechanism was revealed.

Results: Forty-nine PDX models were established (take rate: 55.1%). Successful PDX engraftment was associated with negative HbsAg (P = 0.031), presence of mVI (P = 0.001), poorer tumor differentiation (P = 0.023), multiple tumor number (P = 0.003), presence of lymph node metastasis (P = 0.001), and later TNM stage (P = 0.039). Moreover, patients with tumor engraftment had significantly shorter time to recurrence (TTR) (P < 0.001) and worse overall survival (OS) (P < 0.001). Multivariate analysis indicated that PDX engraftment was an independent risk factor for shortened TTR (HR = 1.84; 95% CI, 1.05-3.23; P = 0.034) and OS (HR = 2.13; 95% CI, 1.11-4.11; P = 0.024). PDXs were histologically and genetically similar to their parental tumors. We also applied IMF-138 and IMF-114 PDX drug testing results to guide clinical treatment for patients with ICC and found similar treatment responses. PDX models also facilitated personalized medicine for patients with ICC based on drug screening results using whole exome sequencing data. Additionally, PDX models reflected the heterogeneous sensitivity to lenvatinib treatment and CDH1 might be vital to lenvatinib-resistance.

Conclusion: PDX models provide a powerful platform for preclinical drug discovery, and potentially facilitate the implementation of personalized medicine and improvement of survival of ICC Cancer patient.

Keywords

drug resistance; intrahepatic cholangiocarcinoma; lenvatinib; patient derived xenograft; personalized medicine.

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