MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.

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Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BMC Cancer ◽

10.1186/1471-2407-9-101 ◽

2009 ◽

Vol 9 (1) ◽

Cited By ~ 24

Author(s):

Alessandra Fabi ◽

Giulio Metro ◽

Michelangelo Russillo ◽

Antonello Vidiri ◽

Carmine Maria Carapella ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Detection of MGMT promoter methylation in malignant gliomas.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e23131 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e23131-e23131

Author(s):

Michelle Afkhami ◽

Vandana Sharma ◽

Maria Cuellar ◽

Massimo D'Apuzzo ◽

Behnam Badie ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2013 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2013-2013

Author(s):

Wolfgang Wick ◽

Tobias Kessler ◽

Michael Platten ◽

Christoph Meisner ◽

Michael Bamberg ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Predictive Biomarker ◽

Copy Number Variations ◽

Mgmt Promoter Methylation ◽

Published Data ◽

Global Methylation ◽

Methyl Transferase ◽

Mgmt Promoter

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.

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MGMT promoter methylation in malignant gliomas

Targeted Oncology ◽

10.1007/s11523-010-0153-6 ◽

2010 ◽

Vol 5 (3) ◽

pp. 161-165 ◽

Cited By ~ 43

Author(s):

Markus J. Riemenschneider ◽

Monika E. Hegi ◽

Guido Reifenberger

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Immunotherapeutic early-phase clinical trials and malignant gliomas: a single-center experience and comprehensive immunophenotyping of circulating leukocytes

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab160 ◽

2021 ◽

Author(s):

Matteo Simonelli ◽

Pasquale Persico ◽

Arianna Capucetti ◽

Claudia Carenza ◽

Sara Franzese ◽

...

Keyword(s):

Clinical Trials ◽

Promoter Methylation ◽

Early Phase ◽

Univariate Analysis ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Control Group ◽

Large Expansion ◽

Mgmt Promoter ◽

Early Phase Clinical Trials

Abstract Background Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of p <0.1. Results Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti PD-1, anti CSF-1R, anti TGFβ, anti cereblon), fifteen patients combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than six years. Univariate analysis identified O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

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ACTR-05. PROCARBAZINE AND CCNU CHEMOTHERAPY FOR RECURRENT GLIOBLASTOMA WITH MGMT PROMOTER METHYLATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.049 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi13-vi13

Author(s):

Yong Kil Hong ◽

Seung Ho Yang

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Target Therapy ◽

Malignant Gliomas ◽

Chemotherapeutic Agents ◽

Recurrent Glioblastoma ◽

Mgmt Promoter Methylation ◽

Recurrent Glioblastoma Multiforme ◽

Serious Adverse Events ◽

Mgmt Promoter

Abstract BACKGROUND While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6). RESULTS One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM

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Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.5964 ◽

2008 ◽

Vol 26 (25) ◽

pp. 4189-4199 ◽

Cited By ~ 499

Author(s):

Monika E. Hegi ◽

Lili Liu ◽

James G. Herman ◽

Roger Stupp ◽

Wolfgang Wick ◽

...

Keyword(s):

Promoter Methylation ◽

Tumor Tissue ◽

Alkylating Agents ◽

Malignant Gliomas ◽

Chemotherapy Resistance ◽

Mgmt Promoter Methylation ◽

Hematologic Toxicity ◽

Major Mechanism ◽

Mgmt Promoter ◽

Methylguanine Methyltransferase

Resistance to alkylating agents via direct DNA repair by O6-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O6-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

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