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Correlation of O⁶-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

Monika E. Hegi, Lili Liu, James G. Herman, Roger Stupp, Wolfgang Wick, Michael Weller, Minesh P. Mehta, Mark R. Gilbert

From the Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne; National Center of Competence in Research Molecular Oncology, Lausanne; Department of Neurology, University Hospital Zurich, Zurich, Switzerland; Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH; Department of Oncology–Cancer Biology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neuro-Oncology, UniversitätsKlinikum Heidelberg, Heidelberg, Germany; Department of Human Oncology, University of Wisconsin Medical School, Madison, WI; and the Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Corresponding author: Monika E. Hegi, PhD, Laboratory of Tumor Biology and Genetics, Department of Neurosurgery BH-19-110, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland; e-mail: monika.hegi{at}chuv.ch

Resistance to alkylating agents via direct DNA repair by O⁶-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O⁶-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

Supported in part by Schering-Plough International (funding for medical editorial assistance).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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