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
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.
Available from: Clément N David
- "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.
ASN Neuro 01/2015; 7(1). DOI:10.1177/1759091415572365 · 4.02 Impact Factor
Available from: Antonio Gomez
- "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) , as well as homozygous deletion of CDKN2A/p14(ARF)/CDKN2B in six out of ten tumors analyzed in a different cohort . "
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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.
BMC Cancer 03/2014; 14(1):213. DOI:10.1186/1471-2407-14-213 · 3.36 Impact Factor
Available from: Walter J Curran
- "More striking is the long-term follow-up data for temozolomide and radiotherapy, which reveals that 9.8% of patients treated with concurrent therapy were alive at 5 years . This point is further magnified when methyl-guanine methyl transferase gene (MGMT) methylation, which has been previously shown to be an independent prognostic indicator and predictor of benefit from temozolomide, is considered [2,5-8]. In those patients with MGMT methylation treated with a combination of temozolomide and radiotherapy the 5-year overall survival (OS) was shown to be as high as 13.8% . "
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ABSTRACT: To dosimetrically evaluate the effect of reduced margin radiotherapy on hippocampal dose for glioblastoma multiforme (GBM) patients.
GBM patients enrolled on the Radiation Therapy Oncology Group (RTOG) 0825 trial at our institution were identified. Standard RTOG 0825 expansions were 2 cm + 3-5 mm from the gross tumor volume (GTV) to the clinical tumor volume (CTV) and from the CTV to the planning tumor volume (PTV), respectively. These same patients also had reduced margin tumor volumes generated with 8 mm (GTV to CTV) + 3 mm (CTV to PTV) expansions. Individual plans were created for both standard and reduced margin structures. The dose-volume histograms were statistically compared with a paired, two-tailed Student's t-test with a significance level of p < 0.05.
A total of 16 patients were enrolled on RTOG 0825. The reduced margins resulted in statistically significant reductions in hippocampal dose at all evaluated endpoints. The hippocampal Dmax was reduced from a mean of 61.4 Gy to 56.1 Gy (8.7%), D40% was reduced from 49.9 Gy to 36.5 Gy (26.9%), D60% was reduced from 32.7 Gy to 18.7 Gy (42.9%) and the D80% was reduced from 27.3 Gy to 15.3 Gy (44%).
The use of reduced margin PTV expansions in the treatment of GBM patients results in significant reductions in hippocampal dose. Though the exact clinical benefit of this reduction is currently unclear, this study does provide support for a future prospective trial evaluating the neurocognitive benefits of reduced margin tumor volumes in the treatment of GBM patients.
Radiation Oncology 01/2014; 9(1):20. DOI:10.1186/1748-717X-9-20 · 2.55 Impact Factor
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