Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers

PLoS One. 2015 Mar 31;10(3):e0121872. doi: 10.1371/journal.pone.0121872. eCollection 2015.

Abstract

The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / pathology
  • Esophagogastric Junction / pathology*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Associated data

  • GEO/GSE58870

Grant support

GL was supported by the Alan B. Brown Chair in Molecular Genomics, Posluns Family Fund and CCO Chair in Experimental Therapeutics and Population Studies. This study was conducted with the support of the Ontario Institute for Cancer Research to PCB through funding provided by the Government of Ontario. LEA was supported by an Ontario Institute for Cancer Research New Investigator Award. PCB was supported by a Terry Fox Research Institute New Investigator Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.