The EGF receptor family as targets for breast cancer therapy

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Breast tumors express high levels of type I receptor tyrosine kinases and their ligands. This receptor family is composed of four homologue receptors; the epidermal growth factor receptor (ErbB1/EGF receptor/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). These receptors are composed of an extracellular binding domain, a transmembrane lipophilic segment, and an intracellular protein tyrosine kinase domain with a regulatory carboxyl terminal segment. Several lines of evidence suggest that these receptors are optimal targets for new anti-cancer agents, and a series of monoclonal antibodies are currently being evaluated both in the laboratory and in the clinic. Agents currently under study include monoclonal antibody (MAb) C225 directed at the EGFR, tratstuzumab (Herceptin^®) directed at the HER2 receptor, and a new family of specific EGFR tyrosine kinase inhibitors.

Anti-EGFR MAb 225 prevents the binding of the ligands to the EGFR, blocks ligand-induced activation of the receptor, and inhibits the growth of cancer cells both in tissue culture and in human tumor xenografts. Anti-EGFR MAb 225 greatly enhances the antitumor effects of chemotherapeutic agents active against breast cancer, such as taxol and doxorubicin. A human:murine `chimeric' antibody (C225) has been produced with comparable affinity and antitumor activity that allows the administration of repeated doses of MAb either alone or in combination with chemotherapy. Initial phase I clinical trials of single and multiple dose weekly administration of C225 have shown that the antibody is safe and with predictable pharmacology, achieving optimal antibody serum levels for a prolonged period of time.

A new family of potent EGFR tyrosine kinase inhibitors (TKI) has been recently shown to have a high degree of receptor specificity and very potent antitumor activity in the laboratory. We are currently conducting a phase I clinical trial with ZD1839, a potent EGFR TKI, in patients with advanced malignancies. We have observed inhibition in vivo of receptor function by tumor and skin biopsies, and anti-responses have been observed.