WINDOW consortium: A path towards increased therapy efficacy against glioblastoma

Abdul, Kulsoom U.; Houweling, Megan; Svensson, Fredrik; Narayan, Ravi S.; Cornelissen, Ferry; Küçükosmanoğlu, Aslı; Metzakopian, Emmanouil; Watts, Colin; Bailey, David; Würdinger, Tom; Westerman, Bart A.

doi:10.1016/j.drup.2018.10.001

Cited by 17 publications

(12 citation statements)

References 87 publications

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“…Our results based on drug induced gene expression analysis support the orthogonal screening strategy being adopted within the WINDOW Consortium [73]. U87MG glioblastoma cells display a coordinated survival response upon LY-294002 treatment, involving both PI3K and JAK2.…”

Section: Plos Onesupporting

confidence: 68%

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Pruteanu¹,

Kopanitsa²,

Módos

et al. 2020

PLoS ONE

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Pathway analysis is an informative method for comparing and contrasting drug-induced gene expression in cellular systems. Here, we define the effects of the marine natural product fucoxanthin, separately and in combination with the prototypic phosphatidylinositol 3kinase (PI3K) inhibitor LY-294002, on gene expression in a well-established human glioblastoma cell system, U87MG. Under conditions which inhibit cell proliferation, LY-294002 and fucoxanthin modulate many pathways in common, including the retinoblastoma, DNA damage, DNA replication and cell cycle pathways. In sharp contrast, we see profound differences in the expression of genes characteristic of pathways such as apoptosis and lipid metabolism, contributing to the development of a differentiated and distinctive drug-induced gene expression signature for each compound. Furthermore, in combination, fucoxanthin synergizes with LY-294002 in inhibiting the growth of U87MG cells, suggesting complementarity in their molecular modes of action and pointing to further treatment combinations. The synergy we observe between the dietary nutraceutical fucoxanthin and the synthetic chemical LY-294002 in producing growth arrest in glioblastoma, illustrates the potential of nutripharmaceutical combinations in targeting this challenging disease.

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Section: Plos Onesupporting

confidence: 68%

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Pruteanu¹,

Kopanitsa²,

Módos

et al. 2020

PLoS ONE

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“…GBM is highly invasive, infiltrating the surrounding brain parenchyma, but the lesions are typically confined to the central nervous system [3,4]. The survival of patients with GBM remains poor despite standard surgery, radiation and chemotherapy [5]. Recently, large-scale genome-wide profiling studies yielded an abundance of genome data and provided deeper insights into the molecular pathogenesis of glioma [2,6].…”

Section: Introductionmentioning

confidence: 99%

UBE2T promotes glioblastoma invasion and migration via stabilizing GRP78 and regulating EMT

Huang

Guo

Zhao

et al. 2020

Aging

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Glioblastoma (GBM) generally has a dismal prognosis, and it is associated with a poor quality of life as the disease progresses. However, the development of effective therapies for GBM has been deficient. Ubiquitin-conjugating enzyme E2T (UBE2T) is a member of the E2 family in the ubiquitin-proteasome pathway and a vital regulator of tumour progression, but its role in GBM is unclear. In this study, we aimed to clarify the role of UBE2T in GBM. Bioinformatics analysis identified UBE2T as an independent risk factor for gliomas. Immunohistochemistry was used to measure UBE2T expression in GBM and normal tissue samples obtained from patients with GBM. The effects of UBE2T on GBM cell invasion and migration were analysed using the Transwell assay. BALB/c nude mice were used for the in vivo assays. Immunoblotting and immunoprecipitation were performed to determine the molecular mechanisms. UBE2T was highly expressed in GBM tissues, and its expression was linked to a poor prognosis. In vitro, depletion of UBE2T significantly suppressed cell invasion and migration. Moreover, UBE2T depletion suppressed the growth of GBM subcutaneous tumours in vivo. Further experiments revealed that UBE2T suppressed invasion and migration by regulating epithelial- mesenchymal transition (EMT) via stabilising GRP78 in GBM cells. We uncovered a novel UBE2T/GRP78/EMT regulatory axis that modulates the malignant progression and recurrence of GBM, indicating that the axis might be a valuable therapeutic target.

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“…(Cunha ML 2019) In addition, there are still controversies as to whether systemic adjuvant treatment can be administered after surgery considering potential adverse effects or tumor heterogeneity. (Abdul KU 2018) Therefore, it is essential to identify critical biomarkers to estimate GBM prognosis. In the current premise, an immune-related gene (IRGs)-based prognostic signature was explored as a comprehensive method to de ne the prognosis of glioblastoma (GBM) and provided importance in most analyses.…”

Section: Discussionmentioning

confidence: 99%

A Six-Immune-Related Genes Prognostic Signature for Glioblastoma

Huang¹,

Rao²,

Lu³

et al. 2021

Preprint

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Background: Glioblastoma (GBM) multiforme is a common malignant brain tumor with high mortality. It is urgently necessary to develop a new treatment because traditional approaches have reached a bottleneck.Purpose: Here we created an immune-related gene (IRGs)-based prognostic signature to comprehensively define the prognosis of glioblastoma (GBM).Methods: Glioblastoma samples were abstracted from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Omnibus (GEO). We retrieved IRGs from the ImmProt data resource. Univariate Cox analysis was adopted to determine the prognostically remarkable IRGs for individual with GBM. The prognostically optimal IRGs were determined via LASSO regression, and predictive model created. Besides, the association of specific factors with the overall survival (OS) of individuals with GBM was explored via multivariate Cox-regression. Lastly, we constructed a predictive nomogram integrating the independent predictive factors to determine the one-, two-, and three-year OS likelihoods of individuals with GBM. Additionally,gene set enrichment analysis(GSEA) and single sample GSEA(ssGSEA) were performed to understand the correlation between the risk score and immune activity.Results: Overall, 273 IRGs which exhibited differential expression were identified in GBM tumor in contrast with the non-malignant samples. Of these 273 IRGs, only six were remarkably linked to OS of individuals with GBM, which were employed in constructing the predictive signature. The GBM were categorized into either the high-risk GBM group or the low-risk GBM group. There were remarkable differences between the high-risk GBM and the low-risk GBM groups regarding OS. The AUC for predicting one-,two-, and three-year OS in training set was 0.610,0.698 and 0.694.In line with the AUC of validation set was 0.608,0.692 and 0.678.Besides,the results of ssGSEA showed the score of prognostic signature is closely related to immune activity.Conclusion: Herein, a robust predictive model based on IRGs was created to estimate the diversity of OS likelihoods in GBM patients, as well as aid future clinical research.

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WINDOW consortium: A path towards increased therapy efficacy against glioblastoma

Cited by 17 publications

References 87 publications

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

Transcriptomics predicts compound synergy in drug and natural product treated glioblastoma cells

UBE2T promotes glioblastoma invasion and migration via stabilizing GRP78 and regulating EMT

A Six-Immune-Related Genes Prognostic Signature for Glioblastoma

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