A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) autocrine pathway contributes t o a number of processes important to cancer development and progression, in cluding cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. The results of a la rge body of preclinical studies and the early clinical trials thus far cond ucted suggest that targeting the EGFR could represent a significant contrib ution to cancer therapy. A variety of different approaches are currently be ing used to target the EGFR. The most promising strategies in clinical deve lopment include monoclonal antibodies to prevent ligand binding and small m olecule inhibitors of the tyrosine kinase enzymatic activity to inhibit aut ophosphorylation and downstream intracellular signaling. At least five bloc king monoclonal antibodies have been developed against the EGFR. Among thes e, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cance r patients in Phase II and III studies, alone or in combination with conven tional therapies, such as radiotherapy and chemotherapy. A number of small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity is also in development. OSI-774 and ZD1839 (Iressa) are currently in Phase II and I II development, respectively. ZD1839, a p.o. active, selective quinazoline derivative has demonstrated promising in vitro and in vivo antitumor activi ty. Preliminary, results from Phase I and II trials in patients with advanc ed disease demonstrate that ZD1839 and OSI-774 have an acceptable tolerabil ity profile and promising clinical efficacy in patients with a variety of t umor types. This mini-review describes the EGFR inhibitors in clinical deve lopment.