© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 12, 851-867,
June 18, 2003
© 2003 Oxford University Press
REVIEW |
Developing Inhibitors of the Epidermal Growth Factor Receptor for Cancer Treatment
Affiliation of authors: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
Correspondence to: Manuel Hidalgo, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Bldg. 1M88, 1650 Orleans St., Baltimore, MD 21231–1000 (e-mail: mhidalg1{at}jhmi.edu).
Progress in identifying and understanding the molecular and cellular causes of cancer has led to the discovery of anomalies that characterize cancer cells and that represent targets for the development of cancer therapeutics. One such target is the epidermal growth factor receptor (EGFR), a transmembrane protein that is frequently dysregulated in cancer cells. Preclinical studies have demonstrated that pharmacologic interventions that abrogate EGFR dysfunction result in antitumor effects. On the basis of these findings, therapeutic strategies to inhibit EGFR and EGFR-related pathways, including the use of monoclonal antibodies against the extracellular ligand-binding domain of EGFR and small-molecule inhibitors of the tyrosine kinase activity of EGFR, have entered clinical testing where they have demonstrated favorable safety profiles and adequate clinical pharmacology. Further development of these agents has been fueled by evidence of their antitumor activities, both as single agents and in combination with chemotherapy and radiation therapy. Areas that require investigation are the definition of patient populations most likely to derive benefits from these drugs, the implementation of biologic correlative studies to aid the selection of pharmacodynamically relevant doses and schedules, the characterization of population pharmacokinetic parameters and pharmacogenomic variables, and the most appropriate clinical scenario for proceeding with the clinical development of these agents.
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