HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with limited therapeutic options, a high recurrence rate and mortality. Standard therapy is maximal surgical resection and radiotherapy (RT). Recent data suggest combining temozolomide with RT is better than RT alone. Adjuvant chemotherapy has a modest impact on survival. For relapsed patients there is no standard therapy, but options include chemotherapeutic agents or new agents in development. One approach to improve outcome is using targeted agents that interfere with cell-surface receptors or intracellular signaling pathways. Between 40% and 50% of GBM tumors show HER1/EGFR dysregulation, and almost half co-express the constitutively active mutant receptor subtype EGFRvIII, which may contribute to the aggressive and refractory course of GBM. Numerous studies show a relationship between aberrant HER1/EGFR biology and tumorigenicity in GBM cells. Two available HER1/EGFR tyrosine kinase inhibitors (TKIs) are gefitinib (Iressa) and erlotinib (Tarceva); both show antitumor and radiosensitization effects in vitro and in animal models of GBM. Clinical trials in patients with GBM and other gliomas are ongoing. Preliminary and published results from trials of gefitinib in recurrent GBM show no increased time to progression or overall survival (OS) compared with historical controls. Studies with erlotinib show greater antitumor activity in patients with GBM than with gefitinib, although the impact of both agents on OS remains unclear. GBM treatment with HER1/EGFR TKIs alone or combined with other targeted therapies and conventional modalities deserve further investigation and refinement, as does our understanding of their mechanisms of action and the role of genetics.