ArticleStem cells (Dayton, Ohio)2014
A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor-initiating cells.
Article in Stem cells (Dayton, Ohio), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 128 citations in OpenAlex.
- A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma.Neurosurgery · 2021Trial
- Targeting NOTCH-immune crosstalk in gliomas: from mechanisms to therapeutics.Frontiers in oncology · 2026Review
- Developmental exposure to methyl ester sulfonate induces autism-like behavioral deficits in mice by dysregulation of the Notch/Hes signaling pathway disrupting neuronal differentiation.Archives of toxicology · 2025Article
- Dual molecular therapy targeting tumor cell heterogeneity improves therapeutic efficacy in glioblastoma.iScience · 2025Article
- Phenotypic variations in glioma stem cells: regulatory mechanisms and implications for therapeutic strategies.Journal of translational medicine · 2025Review
- Ioning out glioblastoma: ferroptosis mechanisms and therapeutic frontiers.Cell death discovery · 2025Review
- Cancer stem cells: landscape, challenges and emerging therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Metabolism and signaling crosstalk in glioblastoma progression and therapy resistance.Molecular oncology · 2025Review
- Notch and Hedgehog Signaling Unveiled: Crosstalk, Roles, and Breakthroughs in Cancer Stem Cell Research.Life (Basel, Switzerland) · 2025Review
- NOTCH3 Mutation Causes Glymphatic Impairment and Promotes Brain Senescence in CADASIL.CNS neuroscience & therapeutics · 2025Article
- The Glioblastoma Landscape: Hallmarks of Disease, Therapeutic Resistance, and Treatment Opportunities.Medical research archives · 2023Article
- EGFR suppresses p53 function by promoting p53 binding to DNA-PKcs: a noncanonical regulatory axis between EGFR and wild-type p53 in glioblastoma.Neuro-oncology · 2022Article
- Alternative RNA splicing modulates ribosomal composition and determines the spatial phenotype of glioblastoma cells.Nature cell biology · 2022Article
- Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma.Cells · 2022Review
- Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies.Biomedicines · 2022Review
- Tumor Microenvironment in Glioma Invasion.Brain sciences · 2022Review
- Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.Developmental cell · 2022Article
- PDPN marks a subset of aggressive and radiation-resistant glioblastoma cells.Frontiers in oncology · 2022Article
- Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Integrated Gene Expression and Methylation Analyses Identify DLL3 as a Biomarker for Prognosis of Malignant Glioma.Journal of molecular neuroscience : MN · 2021Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor-initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and nonresponders. Responder GICs had an enriched proneural gene signature in comparison to nonresponders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2, and so on, enriched in responder group. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ secretase inhibitors might be of potential value to treat that particular group of proneural glioblastoma (GBM). Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.