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Published on: June 2, 2023
Patient-Derived Xenograft Models for Intrahepatic Cholangiocarcinoma and Their Application in Guiding Personalized
Yang Gao1, Rong Zhou2, Jun-Feng Huang3
1Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
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.
Insights
Patient-derived xenograft (PDX) models accurately reflect intrahepatic cholangiocarcinoma (ICC) diversity, aiding personalized medicine and identifying lenvatinib resistance mechanisms. These models improve preclinical drug discovery for intractable ICC.
Area of Science:
- Oncology
- Translational Research
- Cancer Models
Background:
- Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with limited effective treatments.
- Reliable tumor models are crucial for developing new therapies for ICC.
- Patient-derived xenograft (PDX) models offer a promising approach to study ICC biology and therapeutic vulnerabilities.
Purpose of the Study:
- To establish and evaluate patient-derived xenograft (PDX) models for intrahepatic cholangiocarcinoma (ICC).
- To explore the application of PDX models in guiding personalized medicine for ICC.
- To identify potential biomarkers associated with lenvatinib resistance in ICC.
Main Methods:
- Generated 89 ICC patient-derived xenograft (PDX) models.
- Compared morphological and molecular similarities between parental tumors and PDXs.
- Analyzed clinicopathologic features, prognostic significance, and drug treatment responses, including lenvatinib resistance mechanisms.
Main Results:
- Established 49 PDX models (55.1% take rate).
- PDX engraftment correlated with specific clinicopathologic features and predicted poorer patient outcomes (shorter time to recurrence, worse overall survival).
- PDX models demonstrated similar treatment responses to parental tumors and facilitated personalized medicine strategies, revealing CDH1's potential role in lenvatinib resistance.
Conclusions:
- PDX models are valuable for preclinical drug discovery in ICC.
- PDX models can aid in implementing personalized medicine for ICC patients.
- These models hold potential for improving survival outcomes in ICC.
