Magazine article Drug Topics

EGFRs: New Class of Cancer Therapy on the Horizon

Magazine article Drug Topics

EGFRs: New Class of Cancer Therapy on the Horizon

Article excerpt

The epidermal growth factor receptor (EGFR) has recently become the focus of clinical research because it plays an important role in the uncontrolled growth of several human cancers. Speaking at a teleconference on EGFR-targeted therapies, Alan Sandler, M.D., associate professor, Vanderbilt-Ingram Cancer Center, Nashville, said that deregulation of the EGFR is a significant factor in the genesis and progression of various cancers, including those of the brain, breast, lung, ovary, pancreas, and prostate.

The EGFR drives uncontrolled cancer cell growth by the inhibition of apoptosis, which leads to angiogenesis and metastases, Sandler explained. The EGFR is overexpressed in malignant tissue, he said. He also mentioned that EGFR overexpression is associated with a poor prognosis.

The EGFR belongs to the ErbB family of transmembrane tyrosine kinase growth factor receptors, Sandler said. It consists of three structural domains: an extracellular ligand binding domain, a lipophilic transmembrane domain, and an intracellular tyrosine kinase domain. As described on the Web site www. egfr-info.com, following ligand binding, the EGFR undergoes dimerization that results in autophosphorylation of specific tyrosine residues of the EGFR, providing "docking sites" for the assembly of signal transduction complexes and the direct phosphorylation of specific tyrosine residues in substrate proteins.

Antibodies to the EGFR bind to the extracellular domain and prevent ligand binding, although the EGFR-tyrosine kinase (EGFR-TK) signal can still be activated by intracellular triggers, resulting in EGFR overexpression, said Sandler. EGFR-- TK inhibitors restrain the EGFR-TK signal regardless of the triggering event by blocking the EGFR-TK domain inside the cell, he continued.

Sandler focused the rest of his discussion on the three EGFR-TK inhibitors that are the furthest along in development, ZD-1839 (Iressa, AstraZeneca), erlotinib (Tarceva, Genentech/OSI Pharmaceuticals), and CI-1033 (Pfizer). These agents are currently in phase II/III clinical trials, he said.

In phase I clinical studies, Iressa was found to have antitumor activity across different types of solid tumors, particularly nonsmall cell lung cancer, said Sandler. In addition, durable partial remission, sometimes lasting more than three months, was noted across a wide range of doses.

Symptom improvement in patients treated with Iressa was noted as well. "Investigators were struck by the fact that patients often felt better before tests revealed that their tumors had shrunk," said Sandler. Dose-limiting toxicity was seen at 800 mg per day, and dosages of 250 mg per day and 500 mg per day were chosen for phase II/III clinical trials, he reported. …

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