**1. Introduction**

Glioblastoma represents the most common primary brain tumor in adults. Despite improve‐ ments of multimodal therapy, the prognosis of this disease remains unfavorable. Thus, great efforts have been made to identify therapeutic agents directed against those specific molecular targets whose presence was shown to be associated with worse clinical outcomes. The epidermal growth factor receptor (HER1/EGFR) has been identified as one such target, and different compounds were developed to inhibit HER1/EGFR and/or its mutant form, EGFRvIII. However, clinical trials did not confirm the initial enthusiasm conveyed by promising results from experimental studies. Therefore, a therapeutic approach directed at inhibiting solely HER1/EGFR does not seem to translate into a clinical benefit. In this chapter we discuss the current therapeutic situation in the setting of glioblastoma while putting the spotlight on erlotinib, a HER1/EGFR-targeted small molecule tyrosine kinase inhibitor.

The epidermal growth factor receptor belongs to the HER family of receptors and consists of an extracellular ligand-binding site, a transmembraneous part and an intracellular tyrosine kinase (TK) domain (Wells, 1999). Docking of its ligands, *e.g.,* epidermal growth factor (EGF) or transforming growth factor-α (TGF-α), to the ligand-binding site activates the intrinsic TK. Subsequently, autophosphorylation of specific tyrosine residues within the cytoplasmic catalytic kinase domain of the receptor and initiation of cytoplasmic signaling cascades such as the ras-raf-mitogen-activated protein kinase (MAPK) pathway or the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway occur (Arteaga, 2003; Scagliotti et al., 2004). As a consequence, diverse cellular functions such as proliferation or differentiation are regulated (Wells, 1999).

HER1/EGFR overexpression or ligand-independent activation was found in various epithelial malignancies (Earp et al., 2003). The causative relationship between dysregulation of the HER1/EGFR and neoplastic disorder is explained by the affection of downstream signal transduction which results in impaired apoptosis and/or stimulation of proliferation, tumori‐

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genesis, angiogenesis and invasion (Halatsch et al., 2006). Dysregulated HER1/EGFR signaling may be caused by different mechanisms such as gene amplification resulting in HER1/EGFR overexpression as shown for 40-50% of glioblastoma (Salomon et al., 1995). Mutational changes of the intrinsic receptor structure constitute another mechanism that may lead to pathologically altered HER1/EGFR signaling. The so-called EGFRvIII accounts for approximately 60% of all HER1/EGFR mutants and is characterized by a constitutive activation (Frederick et al., 2000; Karpel-Massler et al., 2010). The expression of EGFRvIII was shown to confer cellular trans‐ formation and enhanced tumorigenicity (Nishikawa et al., 1994).

Currently, a standard of care for the treatment of *recurrent* glioblastoma does not exist. In general, repeated gross tumor resection should be attempted. However, this strategy might not always be appropriate, especially when considering the fact that progressive tumor invasion may significantly increase the risk of provoking neurological deficits. Chemothera‐ peutics that were especially used before the temozolomide era upon tumor relapse include nitrosoureas such as carmustine (BCNU) or lomustine (CCNU) and alkylating agents such as procarbazine. However, the antineoplastic activity of these agents in clinical trials was shown to be rather modest (Rodriguez et al., 1989; Newton et al., 1990; Brandes et al., 2004). Irinotecan (Camptosar®, Pfizer Pharmaceuticals, New York, NY, U.S.A.), an inhibitor of topoisomerase I (Raymond et al., 2003; Reardon, DA et al., 2005), or bevacizumab (Avastin®, Genentech Inc., San Francisco, CA, U.S.A.), a humanized monoclonal antibody targeted to vascular endothelial growth factor (VEGF), represent two compounds that have been introduced more recently for the treatment of recurrent glioblastoma and that showed anti-glioblastoma activity (Stark-

Erlotinib in Glioblastoma – A Current Clinical Perspective

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**3. Why interfering with HER1/EGFR or EGFRvIII-mediated signaling?**

glioblastoma (Lund-Johansen et al., 1990; Shinojima et al., 2003).

Given the poor therapeutic efficacy of current treatment measures for glioblastoma, the need for different therapeutic strategies is evident. HER1/EGFR is the most frequently amplified gene in glioblastoma, and its overexpression was found in more than half of these tumors which renders HER1/EGFR an outstanding therapeutic target (Salomon et al., 1995). Experi‐ mental studies show that HER1/EGFR stimulates tumor growth, invasion and migration (Lund-Johansen et al., 1990). In addition, data from clinical studies suggest that HER1/EGFR amplification is related to decreased overall survival and worse prognosis in patients with

EGFRvIII represents the most common mutant form of HER1/EGFR and is characterized by constitutive TK activity independent of ligand-binding (Batra et al., 1995; Frederick et al., 2000). Analysis of the expression of HER1/EGFR and EGFRvIII in bioptic glioblastoma specimens suggests concurrent overexpression of both EGFRvIII and HER1/EGFR in most of the tumors (Biernat et al., 2004). Moreover, in an experimental study using a murine model of human glioma xenografts, EGFRvIII expression was found to be related to increased prolifer‐ ation, inhibition of apoptosis, and tumor formation (Nishikawa et al., 1994; Nagane et al., 1996). Other studies showed similar results and identified activation of the MAPK/ERK1/2 and PI3-K/Akt pathways as driving forces of cellular proliferation and tumor progression (Moscatello et al., 1998; Klingler-Hoffmann et al., 2001; Klingler-Hoffmann et al., 2003). In addition, in a murine orthotopic xenograft model of glioblastoma, administration of a mono‐ clonal antibody targeting EGFRvIII (mAb 806) was shown to cause a significant decrease of tumor growth, increase of apoptosis and prolongation of survival (Mishima et al., 2001).

The tumor-specific properties of EGFRvIII have also lead to the development of EGFRvIIItargeted vaccines in order to provoke an immunologic response against EGFRvIII-bearing glioblastoma cells. Potential antitumor efficacy of EGFRvIII-targeted vaccines had been shown

Vance, 2005).

Despite recent improvements, the clinical efficacy of existing therapeutic modalities remains disappointing. Hence, in light of accumulating evidence for HER1/EGFR-mediated promotion of tumor growth and malignant transformation, substantial interest in the realization of HER1/ EGFR-targeted therapeutic strategies developed. Small molecule tyrosine kinase inhibitors such as erlotinib (Tarceva®, Genentech Inc., San Francisco, CA, U.S.A.), a combined inhibitor of both, HER1/EGFR and EGFRvIII, are the clinically most advanced HER1/EGFR-targeted agents (Karpel-Massler et al., 2009). After promising results derived from experimental studies using erlotinib in a single agent approach were not confirmed by clinical trials, hopes now are set on the identification of other targeted agents enhancing the antineoplastic activity of erlotinib in a multi-targeted approach.
