Targeting the epidermal growth factor receptor in high-grade astrocytomas

Abstract

High-grade astrocytomas, including glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), are the most common and aggressive primary malignant brain tumors in adults. Despite improvements in survival with the addition of temozolomide to radiation in the adjuvant setting, the prognosis of patients affected by these tumors remains relatively poor. One approach to improve outcomes in these patients is to target the epidermal growth factor receptor (EGFR). EGFR-targeted therapy is a rational approach since EGFR overexpression and mutant EGFRvIII expression occur in approximately 50% of patients with GBM. Unfortunately, monotherapy with anti-EGFR agents in malignant gliomas has not provided the dramatic results sometimes seen with other targeted therapies, such as imatinib in chronic myelogenous leukemia. Anti-EGFR agents currently being studied in malignant gliomas include the tyrosine kinase inhibitors (TKI), monoclonal antibodies (MAb), and anti-EGFR vaccines. Of all these agents, the tyrosine kinase inhibitors-which include erlotinib and gefitinib-have been the most extensively tested in clinical trials. Retrospective analyses have highlighted co-expression of EGFRvIII and wild-type PTEN (phosphatase and tensin homologue deleted in chromosome 10) as a significant predictor of EGFR TKI response in patients with GBM. As the EGFR signaling pathway is exceptionally complex, newer approaches targeting multiple points in the pathway are being developed to improve treatment efficacy.