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

• Published in: PloS one Vol. 10; no. 3; p. e0121872
• Main Authors: Dodbiba, Lorin, Teichman, Jennifer, Fleet, Andrew, Thai, Henry, Starmans, Maud H W, Navab, Roya, Chen, Zhuo, Girgis, Hala, Eng, Lawson, Espin-Garcia, Osvaldo, Shen, Xiaowei, Bandarchi, Bizhan, Schwock, Joerg, Tsao, Ming-Sound, El-Zimaity, Hala, Der, Sandy D, Xu, Wei, Bristow, Robert G, Darling, Gail E, Boutros, Paul C, Ailles, Laurie E, Liu, Geoffrey
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.03.2015; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Analysis; Animal models; Animals; Biophysics; Breast cancer; Chemotherapy; DNA methylation; Drug testing; Epidermal growth factor receptors; ErbB-2 protein; Esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - pathology; Esophagogastric Junction - pathology; Esophagus; Evolution & development; Experiments; Gene expression; Health aspects; Health care networks; Hospitals; Humans; Informatics; Lung cancer; Markers; Medical prognosis; Medical research; Medical screening; Mice; Mice, Inbred NOD; Mice, SCID; Morbidity; mRNA; Oncology; p53 Protein; Pathology; Patients; Pharmacology; Proteins; RNA; Sensitivity; Sensitivity analysis; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Stroma; Thoracic surgery; Tumor proteins; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Canada; United States > US
• DOI: 10.1371/journal.pone.0121872
• ISSN: 1932-6203

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.