Future Perspectives of Enhancing the Therapeutic Efficacy of Epidermal Growth Factor Receptor Inhibition in Malignant Gliomas

In adults, glioblastoma multiforme (GBM) represents the most common malignant brain tumor (Karpel-Massler et al., 2009). Unfortunately, even with the best available standard of care, patients with this disease still face a poor clinical outcome (Stupp et al., 2005). Based on the discovery of molecular targets that are involved in tumorigenesis and maintenance of the malignant cellular phenotype, new therapeutic strategies were developed. In about half of all glioblastomas, the epidermal growth factor receptor (HER1/EGFR) was shown to be amplified and overexpressed, rendering it an outstanding target in this disease (Libermann et al., 1985; Ekstrand et al., 1991). Thus, great interest was generated in the creation of HER1/EGFR-targeted agents. The clinically most advanced compounds that were developed to target HER1/EGFR for the treatment of GBM are small-molecule tyrosine kinase (TK) inhibitors such as erlotinib (Tarceva, Genentech Inc., San Francisco, CA, U.S.A.). TK inhibitors reversibly bind to the intracellular catalytic TK domain of HER1/EGFR followed by the inhibition of autophosphorylation of the receptor as well as further downstream signaling involving phosphatidylinositol 3-kinase/murine thymoma viral oncogene homolog (PI3-K/AKT) and mitogen-activated protein kinase (MAPK) pathways ( Arteaga, 2001; Busse et al., 2000; Scagliotti et al., 2004). Erlotinib does not only inhibit HER1/EGFR but also EGFRvIII, the most frequent mutant form of HER1/EGFR which is characterized by ligand-independent activation (Chu et al., 1997). In experimental studies, erlotinib was shown to inhibit the expression of genes encoding pro-invasive proteins and to significantly diminish EGFRvIII expression in transfected glioblastoma cells (Lal et al., 2002). Moreover, the extent of erlotinib-mediated inhibition of anchorageindependent growth of glioblastoma-derived cell lines was shown to correlate inversely with the cellular capability to induce HER1/EGFR mRNA (Halatsch et al., 2004). However, clinical studies examining the therapeutic efficacy of erlotinib in the setting of GBM have so far failed to prove a therapeutic benefit (Raizer et al., 2010; van den Bent et al., 2009). In a randomized, controlled phase II trial, only 11.4% of the patients with recurrent glioblastoma treated with erlotinib were free of progression after 6 months compared to 24.1% of the patients treated with temozolomide or carmustine (van den Bent et al., 2009). In addition, overall survival of the two treatment groups was found to be similar (7.7 months for the erlotinib group versus 7.3 months for the temozolomide/carmustine group).