EGF mutant receptor vIII as a molecular target in cancer therapy.

Abstract

In the year 2000, an estimated 1220 100 new cases of invasive cancer will be diagnosed in the United States, and about 552 200 people are expected to die of it (Greenlee et al. 2000). Treatment of cancer has conventionally consisted of surgery, radiation and chemotherapy. Despite improved cancer therapy involving early detection, the surgical removal of solid tumor masses, and the use of radiotherapy, cytotoxic agents, or both, truly effective therapeutic approaches are still lacking and thus urgently needed. Extensive analyses have defined tumor-associated and, less frequently, tumor-specific, surface antigens displayed on the malignant cell surface. Targeting cells selectively through these surface antigens by molecular probes is inherently different from surgery, radiation, and chemotherapy and has been considered as a favored modality for cancer therapy. A considerable effort has been made over the past decade to develop new immunotherapeutic strategies against cancer; recently, such strategies have shown promise (Waksal 1999, Yang et al. 1999, Kreitman et al. 2000). Targeted therapy can be accomplished by using tumor-specific monoclonal antibodies (Mabs) alone or Mabs armed with radionuclides, prodrugs, or toxins, which selectively kill tumor cells while not destroying normal cells. Many growth factors and their receptors play important roles in modulating cell division, proliferation and differentiation, and the possibility of disrupting these processes has led to the development of novel therapeutic agents for cancer treatment. Therefore, growth factor receptors are attractive candidates for targeted therapy, as they are often overexpressed on the surface of cancer cells. Among these, the type I epidermal growth factor (EGF)-related family of tyrosine kinase growth factor receptors are expressed in a broad spectrum of tumor types, which classifies them as one of the most frequently implicated cell-surface markers for human cancers. This family consists of four members: EGF receptor (EGFR), ErbB-2, ErbB-3 and ErbB-4 (Gullick 1998). EGFR was the first cell-surface glycoprotein identified to be amplified and rearranged in glioblastoma multiforme (GBM) and to act