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

Abstract

The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including 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 large body of preclinical studies and the early clinical trials thus far conducted suggest that targeting the EGFR could represent a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling. At least five blocking monoclonal antibodies have been developed against the EGFR. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies, alone or in combination with conventional 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 III development, respectively. ZD1839, a p.o. active, selective quinazoline derivative has demonstrated promising in vitro and in vivo antitumor activity. Preliminary results from Phase I and II trials in patients with advanced disease demonstrate that ZD1839 and OSI-774 have an acceptable tolerability profile and promising clinical efficacy in patients with a variety of tumor types. This mini-review describes the EGFR inhibitors in clinical development.