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Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group

ABSTRACT: The data contains Illumina 450k/EPIC array methylation files from 104 patients of the NOA-08 study comparing temozolomide alone vs. radiotherapy in elderly patients with glioblastoma

ORGANISM(S): Homo sapiens

PROVIDER: GSE122920 | GEO | 2019/10/31

REPOSITORIES: GEO

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Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]

Project description:The data contains Illumina 450k/EPIC array methylation files from 380 glioblastoma patients of the Heidelberg Neuro-Oncology Center

2019-10-31 | GSE122994 | GEO

Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group

Project description:Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group

| PRJNA506921 | ENA

Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]

Project description:Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]

| PRJNA507175 | ENA

Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma.

Project description:BackgroundO6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups.MethodsThis is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients >65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg.ResultsIn the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0-10.0] months for TMZ treatment versus 9.4 [8.1-10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76-1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2-4.1) months vs 4.6 (4.2-5.0) months] did not differ, with HR = 1.02 (0.83-1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] mo and 8.5 [6.9-13.3] mo) versus RT (9.6 [6.4-13.7] mo and 4.8 [4.3-6.2] mo, HR 0.44 [0.27-0.70], P < 0.001 for OS and 0.46 [0.29-0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts.ConclusionMGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

| S-EPMC7594575 | biostudies-literature

BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

Project description:Two cell lines were used for methylation profiling to investigate how BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

2022-12-21 | GSE217515 | GEO

Plasma Mouse LC-MSMS - Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival

Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.

2019-08-20 | PXD007193 | Pride

MGMT enhancer modulates glioma cell sensitivity to temozolomide through long-range regulations of multiple genes

Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.

2020-04-02 | GSE129476 | GEO

Gene profile of glioblastoma cells treated with y15 and temozolomide

Project description:The gene expression profiles were identified in glioblastoma cells treated with FAK inhibitor Y15, temozolomide alone or with combination of Y15 and Temozolomide DBTRG and U87 were treated with FAK inhibitor Y15 at 10 microM for 24 h; U87 cells were treated with Temozolomide 100 microM for 24 h and Y15+temozolomide at the same dose as each agent alone

2013-01-12 | E-GEOD-43452 | biostudies-arrayexpress

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

2018-07-13 | GSE113816 | GEO

STC1 promotes temozolomide resistance of glioblastoma through STAT3-mediated regulation of MGMT.

Project description:Resistance to temozolomide (TMZ) is one of the major challenges for glioblastoma (GBM) therapy while the underlying mechanisms demand further exploration. Tumor-repopulating cells (TRCs) have been proven to be involved in chemotherapy resistentce. We first enriched GBM TRCs by culturing DBTRG cells in 3D soft fibrin gels and performed RNA-seq. By anlyzing the differentially expressed genes (DEGs) between TRCs and 2D conventionally cultured DBTRG cells, we identified the glycoprotein gene Stanniocalcin-1 (STC1), which is highly expressed in TRCs. Our analyses using patient data from CGGA disclosed that high STC1 expression was associated with poor prognosis, high glioma grade and TMZ therapy resistance. Both our in vitro and in vivo expreriments showed that overexpression of STC1 promoted while knockdown of STC1 inhibited GBM cell proliferation and TMZ resistance. Our mechanistic study revealed that STC1 elevated the phosphoralation of STAT3 to increase MGMT expression, which inhibited the TMZ-induced DNA damage and apoptosis. Our study provides rationale for targeting STC1 to overcome TMZ resistance.

2024-04-30 | GSE261684 | GEO

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