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.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Induces Astrocyte Proliferation through the Activation of Transforming-Growth Factor-α/Epidermal Growth Factor Receptor Signaling Pathway

“…In this most common and aggressive primary malignant brain tumor with a poor survival rates, Fn14 mRNA and protein levels were found not only to be markedly increased but also to be directly implicated in the malignant behavior of this tumor (Tran et al, 2003(Tran et al, , 2006. Although it is widely accepted that EGFR ligands/EGFR function as an important autocrine loop in supporting proliferation of highgrade gliomas, clinical trials with anti-EGFR agents in malignant gliomas have shown limited therapeutic efficiency (Voelzke et al, 2008). Because EGFR signaling in glioblastoma development has been widely proven (for review, see Taylor et al, 2012), our data provide a rationale for further studying TWEAK/Fn14 signaling as a potential target for glioma treatment.…”

Cancer-associated IDH mutations: biomarker and therapeutic opportunities

“…High-grade primary GBMs are often associated with activating mutations or amplification of epidermal growth factor receptor and PTEN (phosphatase and tensin homolog) deletion (Voelzke et al, 2008;Huang et al, 2009). Analysis of the relationship between genetic alterations in epidermal growth factor receptor and IDH1/IDH2 in GBMs revealed that amplification of EGFR and IDH1/IDH2 mutations are mutually exclusive events (Sanson et al, 2009).…”

Crosstalk between the urokinase-type plasminogen activator receptor and EGF receptor variant III supports survival and growth of glioblastoma cells

“…The efficacy of EGFR-targeting therapeutics, such as gefitinib and erlotinib, has been evaluated in clinical trials (11,12). Although these agents are active in some patients, tumors typically escape control, reestablishing aggressive growth and invasion.…”