Treatment considerations for MGMT-unmethylated glioblastoma

Taylor, Jennie W.; Schiff, David

doi:10.1007/s11910-014-0507-z

Cited by 60Glioma Diagnosis and TreatmentPARP inhibition in cancer therapyDNA Repair Mechanisms

Treatment considerations for MGMT-unmethylated glioblastoma

Taylor, Jennie W., Schiff, David·2015·Current Neurology and Neuroscience Reports

DOI 10.1007/s11910-014-0507-z

Open this paper in CoChat — free account

Abstract

Prognosis for patients with glioblastoma continues to be limited, despite an aggressive, multimodal treatment including alkylating chemotherapy. Temozolomide, the most widely used alkylating agent in glioblastoma, is cytotoxic to cells by inducing DNA damage but can be rapidly repaired by the protein O (6)-methylguanine DNA methyltransferase (MGMT). In a subset of glioblastomas, the MGMT promoter is methylated, impairing the repair mechanism and conferring chemosensitivity. However, MGMT is overexpressed in 60 % of glioblastomas providing an inherent resistance to alkylating agents and challenging the role of temozolomide in this population. This article reviews the data establishing MGMT promoter methylation as a prognostic factor in glioblastoma and its potential role as a predictor of temozolomide response. It focuses on results from recent studies in newly diagnosed glioblastoma, and the role of temozolomide in MGMT-unmethylated patients. We then turn the discussion to alternatives to temozolomide for newly diagnosed patients as well as therapeutic options at the time of recurrence.

Integrity signals

Registry

Crossref · 10.1007/s11910-014-0507-z

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

About 60% of GBM patients have tumors resistant to TMZ because of elevated MGMT.
“For example, in approximately 60% of patients with GBM, tumors are resistant to TMZ due to high levels of the direct reversal repair protein O6-methylguanine DNA methyltransferase (MGMT).42”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [42]

Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043330 · Cited by 21,807 · see citing works
CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2006-2010
Ostrom, Q. T., Gittleman, H. R., Farah, P., Ondracek, A., Chen, Y., Wolinsky, Y., Stroup, N. E., Kruchko, C. A., & Barnholtz‐Sloan, J. S. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not151 · Cited by 12,049 · see citing works
<i>MGMT</i> Gene Silencing and Benefit from Temozolomide in Glioblastoma
Hegi, M. E., Diserens, A.-C., Gorlia, T., Hamou, M.-F., de Tribolet, N., Weller, M., Kros, J. M., Hainfellner, J. A., Mason, W., Mariani, L., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043331 · Cited by 7,405 · see citing works
Inactivation of the DNA-Repair Gene MGMT and the Clinical Response of Gliomas to Alkylating Agents
Esteller, M., García‐Foncillas, J., Andion, E., Goodman, S. N., Hidalgo, O. F., Vanaclocha, V., Baylin, S. B., & Herman, J. G. (2000) · New England Journal of Medicine · doi:10.1056/nejm200011093431901 · Cited by 2,256 · see citing works
Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
Malmström, A., Grønberg, B. H., Marosi, C., Stupp, R., Frappaz, D., Schultz, H., Abacıoğlu, U., Tavelin, B., Lhermitte, B., Hegi, M. E., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70265-6 · Cited by 1,282 · see citing works
Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia.
Esteller, M., Hamilton, S. R., Burger, P. C., Baylin, S. B., & Herman, J. G. (1999) · PubMed · Cited by 1,253 · see citing works
CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future
Esteller, M. (2002) · Oncogene · doi:10.1038/sj.onc.1205600 · Cited by 1,233 · see citing works
Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial
Wick, W., Platten, M., Meisner, C., Felsberg, J., Tabatabai, G., Simon, M., Nikkhah, G., Papsdorf, K., Steinbach, J. P., Sabel, M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70164-x · Cited by 1,136 · see citing works
Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial
Gilbert, M. R., Wang, M., Aldape, K. D., Stupp, R., Hegi, M. E., Jaeckle, K. A., Armstrong, T. S., Wefel, J. S., Won, M., Blumenthal, D. T., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.49.6968 · Cited by 1,063 · see citing works
A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse
Yung, W. K. A., Albright, R. E., Olson, J., Fredericks, R., Fink, K., Prados, M. D., Brada, M., Spence, A., Hohl, R. J., Shapiro, W., et al. (2000) · British Journal of Cancer · doi:10.1054/bjoc.2000.1316 · Cited by 929 · see citing works
Abbreviated Course of Radiation Therapy in Older Patients With Glioblastoma Multiforme: A Prospective Randomized Clinical Trial
Roa, W., Brasher, P. M. A., Bauman, G. S., Anthes, M., Bruera, E. D., Chan, A., Fisher, B., Fulton, D. S., Gulavita, S. P. P., Hao, C., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.06.082 · Cited by 902 · see citing works
Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials
Newlands, E. S., Stevens, M. F. G., Wedge, S. R., Wheelhouse, R. T., & Brock, C. (1997) · Cancer Treatment Reviews · doi:10.1016/s0305-7372(97)90019-0 · Cited by 819 · see citing works
Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide
Hegi, M. E., Diserens, A., Godard, S., Dietrich, P.-Y., Regli, L., Ostermann, S., Otten, P., van Melle, G., de Tribolet, N., & Stupp, R. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0384 · Cited by 782 · see citing works
MGMT promoter methylation in malignant gliomas: ready for personalized medicine?
Weller, M., Stupp, R., Reifenberger, G., Brandes, A. A., van den Bent, M. J., Wick, W., & Hegi, M. E. (2009) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.197 · Cited by 779 · see citing works
Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
Taal, W., Oosterkamp, H. M., Walenkamp, A., Dubbink, H. J., Beerepoot, L. V., Hanse, M. C. J., Buter, J., Honkoop, A. H., Boerman, D. H., Vos, F. D., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70314-6 · Cited by 759 · see citing works
EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma
Weller, M., van den Bent, M. J., Hopkins, K., Tonn, J. C., Stupp, R., Falini, A., Moyal, E. C., Frappaz, D., Henriksson, R., Balañá, C., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70011-7 · Cited by 754 · see citing works
MGMT testing—the challenges for biomarker-based glioma treatment
Wick, W., Weller, M., van den Bent, M. J., Sanson, M., Weiler, M., von Deimling, A., Plass, C., Hegi, M. E., Platten, M., & Reifenberger, G. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.100 · Cited by 580 · see citing works
Repair of O6-alkylguanine by alkyltransferases
Pegg, A. E. (2000) · Mutation Research/Reviews in Mutation Research · doi:10.1016/s1383-5742(00)00017-x · Cited by 576 · see citing works
The role of DNA mismatch repair in drug resistance
Nebel, S. (1998) · ETH Zürich Research Collection · doi:10.3929/ethz-a-001915508 · Cited by 465 · see citing works
Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma
Stupp, R., Hegi, M. E., Neyns, B., Goldbrunner, R., Schlegel, U. S., Clément, P. M., Grabenbauer, G. G., Ochsenbein, A. F., Simon, M., Dietrich, P.-Y., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.6650 · Cited by 453 · see citing works
Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study
Perry, J., Bélanger, K., Mason, W. P., Fulton, D. S., Kavan, P., Easaw, J. C., Shields, C., Kirby, S., Macdonald, D., Eisenstat, D. D., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.5520 · Cited by 379 · see citing works
Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study.
Jaeckle, K. A., Eyre, H. J., Townsend, J. J., Schulman, S., Knudson, H. M., Belanich, M., Yarosh, D. B., Bearman, S., Giroux, D. J., & Schold, S. C. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.10.3310 · Cited by 297 · see citing works
Efficacy and Tolerability of Temozolomide in an Alternating Weekly Regimen in Patients With Recurrent Glioma
Wick, A., Felsberg, J., Steinbach, J. P., Herrlinger, U., Platten, M., Blaschke, B., Meyermann, R., Reifenberger, G., Weller, M., & Wick, W. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.10.7722 · Cited by 260 · see citing works
Predictive impact of MGMT promoter methylation in glioblastoma of the elderly
Reifenberger, G., Hentschel, B., Felsberg, J., Schackert, G., Simon, M., Schnell, O., Westphal, M., Wick, W., Pietsch, T., Loeffler, M., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.27385 · Cited by 256 · see citing works
Current and future developments in the use of temozolomide for the treatment of brain tumours
Stupp, R., Gander, M., Leyvraz, S., & Newlands, E. S. (2001) · The Lancet Oncology · doi:10.1016/s1470-2045(01)00489-2 · Cited by 254 · see citing works
Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine.
Belanich, M., Pastor, M., Randall, T., Guerra, D., Kibitel, J. T., Alas, L., Li, B., Citron, M. L., Wasserman, P., White, A., et al. (1996) · PubMed · Cited by 244 · see citing works
Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea.
Liu, L., Markowitz, S. D., & Gerson, S. L. (1996) · PubMed · Cited by 235 · see citing works
Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma
Brandes, A. A., Franceschi, E., Tosoni, A., Benevento, F., Scopece, L., Mazzocchi, V., Bacci, A., Agati, R., Calbucci, F., & Ermani, M. (2009) · Cancer · doi:10.1002/cncr.24406 · Cited by 226 · see citing works
Temozolomide for high grade glioma
Hart, M. G., Garside, R., Rogers, G., Stein, K., & Grant, R. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007415.pub2 · Cited by 223 · see citing works
The role of DNA mismatch repair in drug resistance.
Fink, D. A., Aebi, S. P., & Howell, S. B. (1998) · PubMed · Cited by 220 · see citing works
Temozolomide in Elderly Patients With Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial
Pérez‐Larraya, J. G., Ducray, F., Chinot, O. L., Catry‐Thomas, I., Taillandier, L., Guillamo, J., Campello, C., Monjour, A., Cartalat‐Carel, S., Barrié, M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.34.8086 · Cited by 210 · see citing works
Validation of Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation in Glioma
Vlassenbroeck, I., Califice, S., Diserens, A., Migliavacca, E., Straub, J., Stefano, I. D., Moreau, F., Hamou, M., Renard, I., Delorenzi, M., et al. (2008) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2008.070169 · Cited by 198 · see citing works
Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas
Everhard, S., Tost, J., abdalaoui, H. E., Crinière, E., Busato, F., Marie, Y., Gut, I. G., Sanson, M., Mokhtari, K., Laigle–Donadey, F., et al. (2009) · Neuro-Oncology · doi:10.1215/15228517-2009-001 · Cited by 177 · see citing works
Phase 2 study of dose-intense temozolomide in recurrent glioblastoma
Norden, A. D., Lesser, G. J., Drappatz, J., Ligon, K. L., Hammond, S. N., Lee, E. Q., Reardon, D., Fadul, C. E., Plotkin, S. R., Batchelor, T. T., et al. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not040 · Cited by 91 · see citing works
Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres
Sciuscio, D., Diserens, A., Dommelen, K. V., Martinet, D., Jones, G., Janzer, R.-C., Pollo, C., Hamou, M., Kaina, B., Stupp, R., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1931 · Cited by 84 · see citing works
O6-Alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications
HOTTA, T., Saito, Y., Fujita, H., Mikami, T., Kurisu, K., Kiya, K., Uozumi, T., Isowa, G., Ishizaki, K., & Ikenaga, M. (1994) · Journal of Neuro-Oncology · doi:10.1007/bf01052897 · Cited by 70 · see citing works
Enzastaurin before and concomitant with radiation therapy, followed by enzastaurin maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation
Wick, W., Steinbach, J. P., Platten, M., Hartmann, C. J., Wenz, F. K., von Deimling, A., Shei, P., MOREAU, V., Stoffregen, C., & Combs, S. E. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not100 · Cited by 61 · see citing works
The Role of Gene Body Cytosine Modifications in MGMT Expression and Sensitivity to Temozolomide
Moen, E. L., Stark, A. L., Zhang, W., Dolan, M. E., & Godley, L. A. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0924 · Cited by 51 · see citing works
Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study.
Stupp, R., Hegi, M. E., Gorlia, T., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.18_suppl.lba2009 · Cited by 47 · see citing works
Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: First results from the randomized multicenter GLARIUS trial.
Herrlinger, U., Schaefer, N., Steinbach, J. P., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.15_suppl.lba2000 · Cited by 29 · see citing works
Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemoirradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter.
Wick, W., Gorlia, T., van den Bent, M. J., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.2003 · Cited by 19 · see citing works
Survival and quality of life in the randomized, multicenter GLARIUS trial investigating bevacizumab/irinotecan versus standard temozolomide in newly diagnosed, MGMT-non-methylated glioblastoma patients.
Herrlinger, U., Schaefer, N., Steinbach, J. P., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.2042 · Cited by 13 · see citing works
MGMT promoter methylation as a prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: First results from the randomized phase II DIRECTOR trial.
Tabatabai, G., Wick, W., Steinbach, J. P., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.2015 · Cited by 9 · see citing works

Flagged first, then by citations

Sorted by citations

Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist
Wang, H., Cai, S., Bailey, B. J., Reza Saadatzadeh, M., Ding, J., Tonsing-Carter, E., Georgiadis, T. M., Zachary Gunter, T., Long, E. C., Minto, R. E., et al. (2017) · Journal of Neurosurgery · doi:10.3171/2016.1.jns152513 · Cited by 49 · see citing works

A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme
Rønning, P. A., Helseth, E., Meling, T. R., et al. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos153 · Cited by 123 · see citing works
The role of temozolomide in newly-diagnosed glioblastoma multiforme
Jenkinson, M. D. (2008) · British Journal of Neurosurgery · doi:10.1080/02688690802182314
42 A novel approach using accelerated hypo-fractionation-IMRT (AH-IMRT) and temozolomide (TMZ) in patients with glioblastoma multiforme (GBM)
Shenouda, G., Roberge, D., Kavan, P., et al. (2006) · Radiotherapy and Oncology · doi:10.1016/s0167-8140(06)80783-8
Evaluation of tolerance of Temozolomide in different strategies for management of the older person with glioblastoma
Cazal-Bonnel, E., Perrier-Cornet, E., Dupuydupin, E., et al. (2013) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2013.09.126
2. Glioblastoma再発に対しTemozolomideを使用した１例(第35回群馬脳腫瘍研究会)
深沢, 洋., 黒崎, み., 甲賀, 英., et al. (2009) · The Kitakanto Medical Journal

Authors: Taylor, J. W., & Schiff, D.
Affiliations: University of California, San Francisco (US)
University of Virginia (US)
Corresponding author: Schiff, David
ORCID: Taylor, Jennie W.
Schiff, David
Venue: Current Neurology and Neuroscience Reports
Publisher: Springer Science and Business Media LLC
Published: 2014-11-15
Volume: 15
Issue: 1
Pages: 507-507
ISSN: 1528-4042 (ISSN-L)
1534-6293
DOI: 10.1007/s11910-014-0507-z
OpenAlex: W2092030031
Cited by: 60
References: 43
Citations by year: 2026: 2 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 2 · 2015: 2
FWCI: 0.61
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Current Neurology and Neuroscience Reports (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords: glioblastoma, MGMT promoter methylation, O6-methylguanine-DNA methyltransferase, temozolomide, DNA repair, prognostic factors, newly diagnosed glioblastoma, recurrent glioblastoma
MeSH terms: Temozolomide, Brain Neoplasms, Dacarbazine, Glioblastoma, Humans, Neoplasm Recurrence, Local, Prognosis, Promoter Regions, Genetic, DNA Modification Methylases, Antineoplastic Agents, Alkylating, DNA Methylation, Tumor Suppressor Proteins, DNA Repair Enzymes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Treatment considerations for MGMT-unmethylated glioblastoma

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks