Treatment considerations for MGMT-unmethylated glioblastoma.
Prognosis for patients with glioblastoma continues to be limited, despite an aggressive, multimodal treatment including alkylating chemotherapy. Temozolomide, the most widely used alkylating agent in glioblastoma, is cytotoxic to cells by inducing DNA damage but can be rapidly repaired by the protein O (6)-methylguanine DNA methyltransferase (MGMT). In a subset of glioblastomas, the MGMT promoter is methylated, impairing the repair mechanism and conferring chemosensitivity. However, MGMT is overexpressed in 60 % of glioblastomas providing an inherent resistance to alkylating agents and challenging the role of temozolomide in this population. This article reviews the data establishing MGMT promoter methylation as a prognostic factor in glioblastoma and its potential role as a predictor of temozolomide response. It focuses on results from recent studies in newly diagnosed glioblastoma, and the role of temozolomide in MGMT-unmethylated patients. We then turn the discussion to alternatives to temozolomide for newly diagnosed patients as well as therapeutic options at the time of recurrence.
Department of Neurological Surgery, University of California, San Francisco, CA, USA.
Jennie W
JW
Taylor
David
D
Schiff
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide