ArticleThe Journal of clinical investigation2024
PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.
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Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26citing papers in PubMed
15.8field-weighted citation impact, top 1% of its field
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Who cites it
26 citing papers in PubMed, 36 citations in OpenAlex.
- Targeted therapies plus radiotherapy for diffuse intrinsic pontine glioma: the randomized phase 2 BIOMEDE trial.Nature medicine · 2026Trial
- Deciphering the Anti-Tumor Mechanisms of Metformin Through Reprogramming of the Tumor Microenvironment.Cells · 2026Review
- Understanding DMG: current treatment options and prospective solutions using nanoparticles.Drug delivery and translational research · 2026Review
- Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma.Neuro-oncology · 2026Article
- Actions of Midostaurin as Cation Channel and Tyrosine Kinase Inhibitor in Diffuse Intrinsic Pontine Glioma Cell Lines.Cancers · 2026Article
- Targeting one-carbon metabolic vulnerabilities of metastasis with therapeutic potential.bioRxiv : the preprint server for biology · 2026Article
- AI-derived prognostic model identifies high-risk gene signatures in pediatric gliomas.Frontiers in immunology · 2026Article
- Challenges and Innovations in Paediatric Brain Tumour Treatments.Pharmaceutics · 2025Review
- Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas.Neuro-oncology · 2025Review
- Decoding the cancer cell proteome: A delicate equilibrium with the genome and epigenome.Neuro-oncology · 2025Article
- The proteomic landscape of diffuse midline glioma highlights the therapeutic potential of non-histone protein methyltransferases.Neuro-oncology · 2025Article
- Current Advances and Future Directions for Sensitizing Gastric Cancer to Immune Checkpoint Inhibitors.Cancer medicine · 2025Review
- Inhibition of mitochondrial bioenergetics and hypoxia to radiosensitize diffuse intrinsic pontine glioma.Neuro-oncology · 2025Article
- Establishment of xenografts and methods to evaluate tumor burden for the three most frequent subclasses of pediatric-type diffuse high grade gliomas.Journal of neuro-oncology · 2025Article
- Targeting the HLA-E-NKG2A axis in combination with MS-275 enhances NK cell-based immunotherapy against DMG.Journal of experimental & clinical cancer research : CR · 2025Article
- Erianin inhibits the proliferation of lung cancer cells by suppressing mTOR activation and disrupting pyrimidine metabolism.Cancer biology & medicine · 2025Article
- Case Report: Application ofFrontiers in oncology · 2025Article
- Multi-pathway mechanisms of Liujunzi decoction in promoting glioma apoptosis and reversing drug resistance: network pharmacology and experimental validation.Frontiers in pharmacology · 2025Article
- Targeted therapy in pediatric central nervous system tumors: a review from the National Pediatric Cancer Foundation.Frontiers in oncology · 2025Review
- The therapeutic potential of repurposed mebendazole, alone and in synergistic combination with ONC201, in the treatment of diffuse midline glioma.American journal of cancer research · 2025Article
Corrections and comments
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Authors and funding
55 authors at 19 institutions in 4 countries.
Ryan J DuchatelCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Evangeline R JacksonCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Sarah G ParackalCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Dylan KiltschewskijPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Izac J FindlayCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Abdul MannanCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Dilana E StaudtCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Bryce C ThomasCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Zacary P GermonCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Sandra LaternserDIPG/DMG Research Center Zurich, Children's Research Center, Department of Pediatrics, University Children's Hospital Zürich, Zurich, Switzerland.
Padraic S KearneyCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
M Fairuz B JamaluddinSchool of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Alicia M DouglasCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Tyrone BeitakiCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Holly P McEwenCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Mika L PerssonCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Emily A HockeDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Vaibhav JainDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Michael AksuDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Elizabeth E ManningSchool of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Heather C MurrayPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Nicole M VerrillsPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Claire Xin SunCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Paul DanielCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Ricardo E VilainPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
David A Skerrett-ByrneInfertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Brett NixonInfertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Susan HuaPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Charles E de BockChildren's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Yolanda Colino-SanguinoChildren's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Fatima Valdes-MoraChildren's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Maria TsoliChildren's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
David S ZieglerChildren's Cancer Institute, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Murray J CairnsPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Eric H RaabeJohns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nicholas A VitanzaBen Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA.
Esther HullemanPrincess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
Timothy N PhoenixDivision of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
Carl KoschmannDivision of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
Frank AlvaroCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Christopher V DayasSchool of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Christopher L TinkleDepartment of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Helen WheelerDepartment of Radiation Oncology Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
James R WhittleDepartment of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
David D EisenstatChildren's Cancer Centre, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
Ron FiresteinCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Sabine MuellerDIPG/DMG Research Center Zurich, Children's Research Center, Department of Pediatrics, University Children's Hospital Zürich, Zurich, Switzerland.
Santosh ValviDepartment of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital, Nedlands, Washington, Australia.
Jordan R HansfordMichael Rice Centre for Hematology and Oncology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
David M AshleyThe Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University, Durham, North Carolina, USA.
Simon G GregoryDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Lindsay B KilburnCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
Javad NazarianDIPG/DMG Research Center Zurich, Children's Research Center, Department of Pediatrics, University Children's Hospital Zürich, Zurich, Switzerland.
Jason E CainCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Matthew D DunCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
Hunter Medical Research Institute · AUCancer Institute of New South Wales · AUDuke University · USHudson Institute of Medical Research · AUUniversity of Newcastle Australia · AUChildren's National · USJohns Hopkins University · USPrincess Máxima Center · NLRoyal Children's Hospital · AUSeattle Children's Hospital · USSt. Jude Children's Research Hospital · USThe Kids Research Institute Australia · AUThe University of Melbourne · AUThe University of Sydney · AUUniversity Children's Hospital Zurich · CHUniversity of California, San Francisco · USUniversity of Cincinnati Medical Center · USUniversity of Michigan · USWomen's and Children's Hospital · AU
Funding
No grant is acknowledged in the PubMed record.
Abstract
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.
Indexed as
Brain Stem NeoplasmsDiffuse Intrinsic Pontine GliomaGliomaMetforminAnimalsGlucoseHumansMicePhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsTOR Serine-Threonine KinasesTumor MicroenvironmentGlucoseMetforminPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsTOR Serine-Threonine KinasesBrain cancerDrug therapyOncogenesOncologyTherapeutics
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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 Socratic graph.