The epidermal growth factor receptor as a therapeutic target in glioblastoma multiforme and other malignant neoplasms

Abstract

The epidermal growth factor receptor (EGFR) is dysregulated in various tumour types such as glioblastoma multiforme (GBM), breast cancer, ovarian carcinoma, non-small cell lung cancer and other cancers. As the intracellular tyrosine kinase of the EGFR activates signalling cascades leading to cell proliferation, angiogenesis and inhibition of apoptosis, the EGFR represents an attractive target in cancer therapy. In GBM which is the most common primary central nervous system tumour in adults, the EGFR is overexpressed in about 40 to 50% of cases, and almost half of these co-express the mutant receptor subtype EGFRvIII. This EGFR variant is constitutively activated, and thereby may contribute to the aggressive and refractory course of GBM which is associated with a median survival of only 40 to 60 weeks from diagnosis. Various trials are ongoing focusing on EGFR and EGFRvIII as new therapeutic targets in GBM. Anti-EGFR monoclonal antibodies (MAbs), e.g. cetuximab, and tyrosine kinase inhibitors (TKIs), e.g. erlotinib and gefitinib, are the most advanced in clinical development. Several trials are investigating MAbs or TKIs in combination with other agents such as inhibitors of the mammalian target of rapamycin. Other still preliminary approaches targeting the EGFR are small interfering RNA, antisense RNA and ribozymes, which lead to degradation of EGFR mRNA. Further studies are needed to define their clinical potential, to identify biological predictors of response and thus to characterize subgroups of patients who will benefit from treatment with these new agents.