Erlotinib inhibits growth of a patient-derived chordoma xenograft.

Abstract

Chordomas are rare primary bone tumors that occur along the neuraxis. Primary treatment is surgery, often followed by radiotherapy. Treatment options for patients with recurrence are limited and, notably, there are no FDA approved therapeutic agents. Development of therapeutic options has been limited by the paucity of preclinical model systems. We have established and previously reported the initial characterization of the first patient-derived chordoma xenograft model. In this study, we further characterize this model and demonstrate that it continues to resemble the original patient tumor histologically and immunohistochemically, maintains nuclear expression of brachyury, and is highly concordant with the original patient tumor by whole genome genotyping. Pathway analysis of this xenograft demonstrates activation of epidermal growth factor receptor (EGFR). In vitro studies demonstrate that two small molecule inhibitors of EGFR, erlotinib and gefitinib, inhibit proliferation of the chordoma cell line U-CH 1. We further demonstrate that erlotinib significantly inhibits chordoma growth in vivo. Evaluation of tumors post-treatment reveals that erlotinib reduces phosphorylation of EGFR. This is the first demonstration of antitumor activity in a patient-derived chordoma xenograft model and these findings support further evaluation of EGFR inhibitors in this disease.

• Authors: I-Mei Siu, Jacob Ruzevick, Qi Zhao, Nick Connis, Yuchen Jiao, Chetan Bettegowda, Xuewei Xia, Peter C Burger, Christine L Hann, Gary L Gallia
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e78895 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24260133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Quinazolines
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Cell Line, Transformed
• Cell Proliferation (drug effects)
• Chordoma (drug therapy, genetics, metabolism, pathology)
• ErbB Receptors (genetics, metabolism)
• Erlotinib Hydrochloride
• Genome-Wide Association Study
• Heterografts
• Humans
• Mice
• Neoplasm Transplantation
• Protein Kinase Inhibitors (pharmacokinetics)
• Quinazolines (pharmacology)
• Xenograft Model Antitumor Assays