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Transcription profiling of human glioblastoma samples from a homogenous cohort of patients treated within clinical trial with eitehr radiotherapy or radiotherapy and temonzolomide

ABSTRACT: Analysis of 80 glioblastoma specimen of patients treated within clinical trials and 4 samples of "normal" brain tissue (non-tumoral). The data was used to identify factors of resistance to a chemoradiation therapy protocol of radiotherapy and concomitant and adjuvant temozolomide (alkylating agent). Experiment Overall Design: 80 glioblastoma specimen and 4 non-tumoral brain samples

ORGANISM(S): Homo sapiens

SUBMITTER: Monika Hegi

PROVIDER: E-GEOD-7696 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.

Murat Anastasia A Migliavacca Eugenia E Gorlia Thierry T Lambiv Wanyu L WL Shay Tal T Hamou Marie-France MF de Tribolet Nicolas N Regli Luca L Wick Wolfgang W Kouwenhoven Mathilde C M MC Hainfellner Johannes A JA Heppner Frank L FL Dietrich Pierre-Yves PY Zimmer Yitzhak Y Cairncross J Gregory JG Janzer Robert-Charles RC Domany Eytan E Delorenzi Mauro M Stupp Roger R Hegi Monika E ME

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20080601 18

<h4>Purpose</h4>Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide.<h4>Patients and methods</h4>Gene expression profiles of 80 gli ...[more]

PMID: 18565887

Publication: 1/2

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Glioblastoma from a homogenous cohort of patients treated within clinical trial

Project description:Analysis of 80 glioblastoma specimen of patients treated within clinical trials and 4 samples of "normal" brain tissue (non-tumoral). The data was used to identify factors of resistance to a chemoradiation therapy protocol of radiotherapy and concomitant and adjuvant temozolomide (alkylating agent). Keywords: Disease state comparison

2008-06-20 | GSE7696 | GEO

Human cerebrospinal fluid impacts chemo-radiotherapy sensitivities in tumour cells from glioblastoma patients

Project description:Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment comprised of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here we examined the effect of human CSF on glioblastoma (GBM) tumours from 25 patients. We found that CSF induces tumour cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear-protein-1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve GBM patient survival.

2023-10-20 | GSE243501 | GEO

Rational targeting of dynamic tumor subclones in relapsing human glioblastoma

Project description:Glioblastoma therapy relies on the alkylating drug temozolomide (TMZ) administered to irradiated patients post-neurosurgery, which increases overall survival but cannot prevent fatal disease relapse. Using clinical samples and glioblastoma models, we here identify TMZ-driven enrichment of ALDH1A1+ tumor subclones acquiring AKT-dependent drug resistance en route to relapse. We demonstrate that this recurrent phenotype switch is predictable and can be countered by a sequential rather than simultaneous combinatorial treatment approach.

2020-02-12 | GSE145128 | GEO

Genomic Exploration of Distinct Molecular Phenotypes Steering Temozolomide Resistance Development in Patient-Derived Glioblastoma Cells

Project description:Temozolomide resistance is a major obstacle in the therapy of glioblastoma. This is also due to the insufficient understanding of glioma heterogeneity in relation to temozolomide resistance. More in depth biological knowledge would benefit the development of different approaches to tackle the problem from its root. We explored the different outcomes derived from the long-term exposure to temozolomide and identified two different behavioral phenotypes associated to specific categories of pathways. In addition, we investigated the intra-tumoral heterogeneity of these phenotypes revealing the complexity of the temozolomide resistance phenomenon.

2023-10-24 | GSE226202 | GEO

Gliocidin is a nicotinamide mimetic prodrug that targets glioblastoma

Project description:Glioblastoma is incurable and in urgent need of improved therapeutics. We identify a small compound, Gliocidin, that kills glioblastoma cells while sparing nontumor replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels causing nucleotide imbalance, replication stress, and tumor cell death. Gliocidin is a prodrug anabolized into its tumoricidal metabolite, Gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase (NMNAT1) of the NAD+ salvage pathway. The cryo-EM structure of GAD together with IMPDH2 demonstrates its entry, deformation, and blockade of the NAD+ pocket. In vivo, Gliocidin penetrates the blood brain barrier and extends orthotopic murine glioblastoma mouse survival. The DNA alkylating agent, temozolomide, induces Nmnat1 expression causing synergistic tumor killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings Gliocidin to light as a prodrug with potential to improve the survival of glioblastoma patients.

2024-10-30 | GSE277301 | GEO

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

Project description:The AVAglio and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy/temozolomide. To establish whether certain patient subgroups derived OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy assessed for each patient subgroup. A multivariate analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with Proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the Proneural subtype biomarker and treatment arm (P = .023). The group of patients with Mesenchymal and Proneural tumors derived a PFS benefit from bevacizumab, compared with placebo; however, this translated to an OS benefit in the Proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type Proneural glioblastoma may derive OS benefit from first-line bevacizumab treatment. The predictive value of the Proneural subtype observed in AVAglio should be validated in an independent dataset. A total of 349 (bevacizumab arm, n = 171; placebo arm, n = 178) pretreatment specimens from AVAglio patients (total n = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.

2016-07-06 | E-GEOD-84010 | biostudies-arrayexpress

Drug resistance in glioblastoma

Project description:Combined model of in vitro and in vivo resistance to alkylating agents (BCNU and Temozolomide) in glioblastoma multiforme. Three matched pairs of surgical specimens from initial (DI, ME, LX) and repeat (DIR, MER, LXR) tumor resection were used to establish cell lines. Patients received BCNU chemotherapy between the two operations, which rendered the sublines from repeat surgery more resistant to BCNU than those from initial surgery. Each the pre-chemotherapeutic set and the post-chemotherapeutic set of cell lines was selected in vitro for resistance to either BCNU or Temozolomide. 9 in vitro selected sublines were established. Of those 4 (2 selected for BCNU [ME-BCNU, DI-BCNU] and 2 selected for Temozolomide [ME-TMZ, LX-TMZ) were generated from the parental/sensitive pre-chemotherapeutic set and 5 (2 selected for BCNU [DIR-BCNU, MER-BCNU] and 3 selected for Temozolomide [DIR-TMZ, MER-TMZ, LXR-TMZ) from the in vivo resistant post-chemotherapeutic set. The model included a total of 15 sublines. Genome-wide high-resolution gene copy number profiling was performed on each subline using 42,000-feature cDNA microarrays. Utilizing the same microarray platform genome-wide gene expression profiles were generated. Biostatistical tools were employed to identify signatures of resistance to alkylating agents both at the genetic as well as at the transcriptomic levels. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Series_type = Logical Set Keywords: other

2006-01-27 | GSE2221 | GEO

Identification of DHC2 associated nuclear proteins in DHC2 knockdown U87 cells

Project description:The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by MGMT. However, many MGMT-negative glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DHC2 was highly expressed in MGMT-negative recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT-negative glioblastoma patients. In vivo and in vitro, silencing DHC2 enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-negative glioblastoma cells. It is known DHC2 is related to intracellular cargo transportation. To identify the potential interacted “cargo” DHC2 transported and explore the underlying molecular mechanisms of DHC2-midiated DNA damage repair, we performed subcellular proteomic and bioinformatic analyses.

2022-02-28 | PXD012032 | Pride

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

Identification of changes in the LNZ308 HLA immunopeptidome after virotherapy, irradiation and chemotherapy

Project description:Glioblastoma is an aggressive incurable primary malignant brain tumor. Measles virus (MeV) therapy is a promising upcoming treatment strategy with proven preclinical efficacy and clinical safety. Using RNA Sequencing and immunopeptidome analyses, we aimed at identifying a synergistic combination regimen of MeV with conventional therapeutic strategies for glioblastoma patients, i.e. radiotherapy and temozolomide or lomustine, and to understand the underlying molecular mechanism.

2018-02-19 | PXD008984 | Pride

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