Abstract
BackgroundIntrahepatic 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.MethodsWe 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.ResultsForty-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.ConclusionPDX 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.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor, accounting for approximately 10%15% of primary hepatic malignancies [1, 2]
The patient derived xenograft (PDX) model has become a prevalent platform for pre-clinical drug screening due to the ability to recapitulate tumor biology
We successfully established PDX models derived from 49 patients with ICC, with an engraftment rate of 55.1%
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor, accounting for approximately 10%15% of primary hepatic malignancies [1, 2]. Despite considerable advances in understanding ICC complexity of this kind of tumor, the development of an effective antitumor drug for ICC patients hasn’t progressed due to a lack of suitable preclinical models that recapitulate the pathologic, biological, and genetic features of ICC. The use of patient derived xenograft (PDX) models has become an attractive platform for drug development and translational cancer research [7, 8]. The clinical significance of PDX engraftment and its potential applications in guiding personalized medicine still need to be further explored. The development of effective drug treatments for ICC is seriously hampered by the lack of reliable tumor models. 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
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