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

Abstract

Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity AbstractResistance to alkylating agents via direct DNA repair by O(6)-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 O(6)-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. 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 glioblastoma patients with MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably 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. Correlation of MGMT Promoter Methylation With Clinical Outcomes in Glioblastoma and

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

“…42 Once the tumor has developed, decreased DNA repair gene expression can however be beneficial to the patients by increasing the sensitivity of the tumor cells to DNA-damaging therapies, as shown for MGMT hypermethylation in glioblastoma. 43 In our study, patients with high NEIL1 methylation showed a significantly higher recurrence-free survival but this was not apparent after stratification by tumor localization. The statistical power of our study cohort might however be too small for a stratified analysis.…”

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

“…18,19 A biomarker test for MGMT status needs to be standardized, suitable for high-throughput analyses and reproducible in independent laboratories, and must have a clinically relevant cut-off point. The test should allow prospective patient selection and individualized therapy, thereby pursuing the strategy of personalized medicine for patients with brain tumors.…”

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

“…The sensitivity of gliomas to TMZ is tightly correlated to the expression of the DNA repair enzyme MGMT (40). Therefore, we compared MGMT-positive U87 cells (41, 42) with MGMT-negative U343 cells (43) and analyzed the extent of cell death after treatment with 5, 10, and 15 μmol/L of (±)-gossypol and (−)-gossypol either with or without 100 μmol/L TMZ for 96 hours.…”