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


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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    ABSTRACT: Glioblastoma multiforme is an extremely aggressive and invasive form of central nervous system tumor commonly treated with the chemotherapeutic drug Temozolomide. Unfortunately, even with treatment, the median survival time is less than 12 months. 2,9-Di-sec-butyl-1,10-phenanthroline (SBP), a phenanthroline-based ligand originally developed to deliver gold-based anticancer drugs, has recently been shown to have significant antitumor activity in its own right. SBP is hypothesized to initiate tumor cell death via interaction with non-DNA targets, and considering most glioblastoma drugs kill tumors through DNA damage processes, SBP was tested as a potential novel drug candidate against glial-based tumors. In vitro studies demonstrated that SBP significantly inhibited the growth of rodent GL-26 and C6 glioma cells, as well as human U-87, and SW1088 glioblastomas/astrocytomas. Furthermore, using a syngeneic glioma model in mice, in vivo administration of SBP significantly reduced tumor volume and increased survival time. There was no significant toxicity toward nontumorigenic primary murine and human astrocytes in vitro, and limited toxicity was observed in ex vivo tissues obtained from noncancerous mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and recovery assays suggest that SBP induces apoptosis in gliomas. This exploratory study suggests SBP is effective in slowing the growth of tumorigenic cells in the brain while exhibiting limited toxicity to normal cells and tissues and should therefore be further investigated for its potential in glioblastoma treatment.
    Full-text · Article · Jan 2015 · ASN Neuro
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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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    ABSTRACT: The alkylating agent temozolomide (TMZ) represents an important component of current melanoma therapy, but overexpression of O6-methyl-guanine DNA methyltransferase (MGMT) in tumor cells confers resistance to TMZ and impairs therapeutic outcome. We investigated a novel perillyl alcohol (POH)-conjugated analog of TMZ, NEO212, for its ability to exert anticancer activity against MGMT-positive melanoma cells. Human melanoma cells with variable MGMT expression levels were treated with NEO212, TMZ, or perillyl alcohol in vitro and in vivo, and markers of DNA damage and apoptosis, and tumor cell growth were investigated. NEO212 displayed substantially greater anticancer activity than any of the other treatments. It reduced colony formation of MGMT-positive cells up to eight times more effectively than TMZ, and much more potently induced DNA damage and cell death. In a nude mouse tumor model, NEO212 showed significant activity against MGMT-positive melanoma, whereas TMZ, or a mix of TMZ plus POH, was ineffective. At the same time, NEO212 was well tolerated. NEO212 may have potential as a more effective therapy for advanced melanoma, and should become particularly suitable for the treatment of patients with MGMT-positive tumors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Dec 2014 · Cancer Letters
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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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    ABSTRACT: Pleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients. Using a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences. Increasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis. Even taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation.
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