Article

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

University Hospital of Lausanne, Lausanne, Vaud, Switzerland
Clinical Cancer Research (Impact Factor: 8.72). 04/2004; 10(6):1871-4. DOI: 10.1158/1078-0432.CCR-03-0384
Source: PubMed

ABSTRACT

In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy.
The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR.
Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression).
This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

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    • "Even though in vivo experiments corroborated the in vitro data that demonstrated increased apoptosis in SBP-treated groups compared with nontreated controls, the obvious question remains: What is the mechanism by which SBP induces apoptosis? More specifically, is SBPinduced apoptosis a result of a similar mechanism as TMZ, which is thought to methylate guanine residues in the DNA (Srivastava et al., 1998; Hegi et al., 2004; Mutter and Stupp, 2006; Chamberlain et al., 2007; Kim et al., 2010; Poteet et al., 2013)? At first glance, it might be expected that SBP acts as a DNA intercalator, as the compound has significant aromatic character. "
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    • "Considering this large differential , it is therefore not surprising that MGMT-positivity of tumor tissue is known to predict poor response to TMZ therapy [46] [47], and indeed our own in vivo experiment with TMZ confirmed this detriment as well (Fig. 7B). In comparison, NEO212 displayed in vitro IC50s from 13–39 μM in MGMT-positive cells (Table 1) and did exert significant (p < 0.01) therapeutic activity in vivo against strongly MGMT-positive melanoma (Fig. 7B). "
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    • "The pathogenesis of PXA is largely unknown. Nevertheless, a series of molecular studies have described genomic alterations in PXA patients [28,42-48] Chromosomal gains and losses have been associated with PXA pathogenesis, although prevalent losses -frequently involving chromosomes 7 and 9- were observed in grade II astrocytomas of poor prognosis [28,42-44], accounting for a potential inactivating mechanism of tumor suppressor genes. Further genetic studies have also unveiled the high frequency of BRAF V600E mutations in WHO grade II PXAs and PXAs with anaplastic features (65 and 66% of cases, respectively) [48], as well as homozygous deletion of CDKN2A/p14(ARF)/CDKN2B in six out of ten tumors analyzed in a different cohort [46]. "
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