ArticleNeuro-oncology2019
Inhibition of mTORC1 in pediatric low-grade glioma depletes glutathione and therapeutically synergizes with carboplatin.
Article in Neuro-oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 28 citations in OpenAlex.
- A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.Pediatric blood & cancer · 2021Trial
- Mebendazole Shows Antiproliferative and Antimigratory Effects in Paediatric Low-Grade Glioma Models.Oncology research · 2026Article
- Glioblastoma metabolomics: uncovering biomarkers for diagnosis, prognosis and targeted therapy.Journal of experimental & clinical cancer research : CR · 2025Review
- Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma.Aging · 2024Article
- Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from PNOC.Neuro-oncology · 2024Article
- Everolimus in pituitary tumor: a review of preclinical and clinical evidence.Frontiers in endocrinology · 2024Review
- Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario.Pharmaceutics · 2023Review
- Pediatric low-grade glioma models: advances and ongoing challenges.Frontiers in oncology · 2023Review
- Preclinical and Clinical Applications of Metabolomics and Proteomics in Glioblastoma Research.International journal of molecular sciences · 2022Review
- Dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating Obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors.Cell death & disease · 2022Article
- Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models.Frontiers in oncology · 2022Article
- The Mechanisms of Current Platinum Anticancer Drug Resistance in the Glioma.Current pharmaceutical design · 2022Review
- Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression.Frontiers in cell and developmental biology · 2022Review
- Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future.Frontiers in oncology · 2022Review
- Review
- Glioblastoma Metabolomics-In Vitro Studies.Metabolites · 2021Review
- Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas.International journal of molecular sciences · 2021Review
- Conditional reprogramming culture conditions facilitate growth of lower-grade glioma models.Neuro-oncology · 2021Article
- TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma.Cancer letters · 2021Article
- The Prognostic Role of Glutathione Peroxidase 1 and Immune Infiltrates in Glioma Investigated Using Public Datasets.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
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Authors and funding
9 authors at 2 institutions in 1 country.
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Abstract
backgroundPediatric low-grade glioma (pLGG) often initially responds to front-line therapies such as carboplatin, but more than 50% of treated tumors eventually progress and require additional therapy. With the discovery that pLGG often contains mammalian target of rapamycin (mTOR) activation, new treatment modalities and combinations are now possible for patients. The purpose of this study was to determine if carboplatin is synergistic with the mTOR complex 1 inhibitor everolimus in pLGG.
methodsWe treated 4 pLGG cell lines and 1 patient-derived xenograft line representing various pLGG genotypes, including neurofibromatosis type 1 loss, proto-oncogene B-Raf (BRAF)-KIAA1549 fusion, and BRAFV600E mutation, with carboplatin and/or everolimus and performed assays for growth, cell proliferation, and cell death. Immunohistochemistry as well as in vivo and in vitro metabolomics studies were also performed.
resultsCarboplatin synergized with everolimus in all of our 4 pLGG cell lines (combination index <1 at Fa 0.5). Combination therapy was superior at inhibiting tumor growth in vivo. Combination treatment increased levels of apoptosis as well as gamma-H2AX phosphorylation compared with either agent alone. Everolimus treatment suppressed the conversion of glutamine and glutamate into glutathione both in vitro and in vivo. Exogenous glutathione reversed the effects of carboplatin and everolimus.
conclusionsThe combination of carboplatin and everolimus was effective at inducing cell death and slowing tumor growth in pLGG models. Everolimus decreased the amount of available glutathione inside the cell, preventing the detoxification of carboplatin and inducing increased DNA damage and apoptosis.
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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.