About this item:

600 Views | 115 Downloads

Author Notes:

Corresponding Authors: Zhuo Georgia Chen, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA. Phone: 404-778-3977; Fax: 404-778-5520; gzchen@emory.edu; and Dong M. Shin, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA. Phone: 404-778-5990; Fax: 404-778-5520; dmshin@emory.edu

Acknowledgments: We thank Genentech for providing erlotinib for this study. We also thank Dr. Anthea Hammond for her critical reading of the article.

Subject:

Research Funding:

This study was supported by grants from the National Institutes of Health (U01 CA101244 and Specialized Programs of Research Excellence in Head and Neck Cancer, P50 CA128613) to DMS and R01CA0983722, P50CA097190 and the American Cancer Society (to JRG).

Chemoprevention of Head and Neck Cancer by Simultaneous Blocking of Epidermal Growth Factor Receptor and Cyclooxygenase-2 Signaling Pathways: Preclinical and Clinical Studies

Show all authors Show less authors

Tools:

Journal Title:

Clinical Cancer Research

Volume:

Volume 19, Number 5

Publisher:

, Pages 1244-1256

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Purpose We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I). Experimental Design We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer (HNC) cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib. Results The combined treatment inhibited HNC cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell cycle progression at G1 phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK and pS6 levels after treatment, which correlated with clinical response. Conclusion Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic.

Copyright information:

©2013 American Association for Cancer Research

Export to EndNote