Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]
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ABSTRACT:
PROVIDER: PRJNA507175 | ENA |
REPOSITORIES: ENA
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Project description:Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group
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Project description:The data contains Illumina 450k/EPIC array methylation files from 380 glioblastoma patients of the Heidelberg Neuro-Oncology Center
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Project description: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
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Project description:The signalling pathways underpinning cell growth and migration share overlapping components but what determines whether cells grow or move, when exposed to the same extrinsic signal, is unclear. We identify that in epithelial cancer cells cultured in extracellular matrix (ECM) these molecular functions can be uncoupled when signals are transduced through alternate transcript variants of IQSEC1, an ARF GTPase Exchange Factor. IQSEC1 associates with the receptor tyrosine kinase (RTK) Met and acts as an organising centre for phosphoinositide signalling, activating ARF5- and ARF6-dependent PIP5-kinase activity, and scaffolding multiple components of the mTORC2 signalling complex to control Akt activation and cell growth. Expression of IQSEC1 variants containing extended N-terminal regions switch this output from growth to collective invasion by conferring association with the endocytic co-receptor LRP1, thereby enhancing Met internalisation and trafficking. These pro-invasive IQSEC1 variants localise the Met/LRP1/IQSEC1 signalling module to the tips of invasive protrusions to induce PI(3,4,5)P3-dependent collective invasion. Chemical or genetic inhibition of these alternate signalling modules targets growth or invasion, independently. Alternate IQSEC1-ARF GTPase signalling complexes thus control RTK signal output by influencing RTK trafficking and the balance between growth or invasion in epithelial cells. Elevated expression of this IQSEC1-ARF module occurs in prostate cancer patient metastases and predicts poor outcome. IQSEC1 may therefore represent a therapeutic vulnerability in prostate cancer cells.
2021-02-04 | PXD013810 | Pride
Project description:Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors. RNA was isolated from parental U87 (U87_EV) and MGMT-transfected U87 (U87_MGMT) triplicate. Pairwise gene expression differences were compared between the two cell lines. Features selected had more than 2-fold up-or down-regulated (P values of >05, unpaired Studentâs t-test with Bonferroni multiple testing correction) were identified. Database for annotation, visualization, and integrated discovery23 was used to identify enriched gene ontology (GO) biological themes.24 The GO data mining was conducted at a term specificity level 3.25 The EASE score was set at 0.05 and the minimum number of genes in a category was 5.
2012-09-11 | E-GEOD-40776 | biostudies-arrayexpress
Project description:Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O6-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O6-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors.
2012-09-11 | GSE40776 | GEO
Project description:Paediatric low-grade gliomas (LGGs) account for about a third of all brain tumours in children. We conducted a detailed study of DNA methylation to improve our understanding of the biology of pilocytic and diffuse astrocytomas. Comparisons were performed between tumours and normal brain controls from matching location, and between pilocytic and diffuse astrocytomas. Pilocytic astrocytomas were found to have a distinctive signature involving 315 CpG sites, with the majority of the sites (312 CpG sites) hypomethylated in pilocytic astrocytomas. Additionally many of the sites were located within annotated enhancers. The distinct signature in pilocytic astrocytomas was not present in diffuse astrocytomas or in published profiles of other brain tumours and normal brain tissue. On further analysis of the 315 CpG sites, the AP-1 transcription factor complex was predicted to bind within 200bp of a subset of teh 315 differentially methylated CpG sites. We also observed up-regulation of the AP-1 factors, FOS and FOSL1 in pilocytic astrocytomas. Our findings highlight novel epigenetic differences between pilocytic and diffuse astrocytomas, in addition to well-described alterations involving BRAF, MYB and FGFR1.
2016-05-10 | GSE77241 | GEO
Project description:Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity.
2017-12-15 | GSE108098 | GEO
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
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