Treatment resistance and a poor prognosis characterize glioblastoma, with a median survival of less than 15 months. Based on the recent findings in the randomized trial conducted by the EORTC and the NCIC (Stupp et al. N Engl J Med, 2005). concomitant and adjuvant temozolomide (TMZ) and radiotherapy has become the new standard of care for newly diagnosed glioblastoma patients. In order to identify patients benefiting from the addition of the alkylating drug TMZ the epigenetic inactivation of the O-6-methylguanine-DNA methyltransferase (MGMT)gene was evaluated in a candidate gene approach. MGMT is a repair enzyme known to rapidly revert the highly toxic O6-methylguanine to its native state, guanine, in a suicide reaction. Hence, blunting most of the treatment effect of the alkylating drug. Here we tested the relationship of MGMT silencing by promoter methylation with outcome in patients randomized either to initial therapy with the alkylating agent TMZ and radiotherapy (RT) or RT only. The benefit from TMZ was mainly confined to patients whose tumors carried a methylated MGMT gene. At 2 years, 46% of the patients treated with TMZ/radiotherapy and whose tumors had a methylated MGMT promoter survived, compared with only 14% for the patients with an unmethylated MGMT status (overall log-rank P=0.0001). In concordance with the mechanistic link to proficient repair, survival analysis of the non-methylated cases indicated only a marginal temozolomide derived benefit for patients (p=0.062, borderline, logrank test). The MGMT status is under prospective evaluation for prediction of benefit from TMZ therapy. Due to the prominent role of MGMT in resistance to therapy it has become a prime target. Efforts aim at depleting the protein from the tumor cells by non-toxic inhibitors such as O6-benzyl guanine, or by a dose dense schedule of TMZ therapy. However, even in the cohort of patients with a methylated MGMT overall survival remains unsatisfactory and extremely variable, indicating additional mechanisms of treatment resistance. Glioblastoma gene expression profiles have identified new independent mechanisms of resistance to this treatment that may be targeted as part of an improved trial design. To date, the test for the MGMT-methylation status is the only tool available that may direct the choice for alkylating agents in glioblastoma patients, and thus, promote individually tailored therapy. For patients with an un-methylated MGMT gene, unlikely to respond, alternative treatments should be proposed.
AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA