Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05009992 (A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas), which is not on this map. Cited by 45 papers.
0numbers the graph read from it
0cells of the map it votes in
45citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
2 · The registry
The trial behind it
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.
A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression
TypeinterventionalSponsorUniversity of California, San FranciscoRan2021 to 2029Enrolled360ConditionsDiffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Diffuse Midline Glioma, H3 K27M-MutantArmsONC201, Radiation Therapy, Paxalisib, DNX-2401
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
5 · Who and what money
Authors and funding
48 authors.
Evangeline R Jackson *Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0002-2245-9213
Ryan J Duchatel *Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0002-3651-7672
Dilana E Staudt *Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0001-5049-2208
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.ORCID 0000-0001-8967-7242
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.ORCID 0000-0001-7680-6594
Sridevi YadavilliCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC.ORCID 0009-0000-5349-8496
Sarah ParackalCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.ORCID 0000-0003-4128-4073
Shaye GameCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.ORCID 0009-0007-0908-8060
Wai Chin ChongCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.ORCID 0000-0002-7686-5559
W Samantha N JayasekaraCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.ORCID 0000-0002-1828-5919
Marion Le GrandCentre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, Marseille, France.ORCID 0000-0002-4910-1289
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.ORCID 0009-0009-8965-4468
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.ORCID 0000-0001-6169-7946
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.ORCID 0000-0002-3192-5888
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.ORCID 0000-0002-2144-7157
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.ORCID 0000-0002-8233-1553
Tyrone S BeitakiCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0009-0004-5949-4188
Adjanie PatabendigeBrain Barriers Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0003-1550-3084
David A Skerrett-ByrneSchool of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0002-1804-1826
Brett NixonSchool of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0003-2745-8188
Nathan D SmithAnalytical and Biomolecular Research Facility Advanced Mass Spectrometry Unit, University of Newcastle, Callaghan, New South Wales, Australia.ORCID 0000-0002-6868-8513
Bryan DayQIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.ORCID 0000-0002-8948-9089
Neevika ManoharanDepartment of Paediatric Oncology, Sydney Children's Hospital, Randwick, New South Wales, Australia.ORCID 0000-0002-2914-8637
Sumanth NagabushanDepartment of Paediatric Oncology, Sydney Children's Hospital, Randwick, New South Wales, Australia.ORCID 0000-0001-7574-8919
Jordan R HansfordMichael Rice Cancer Centre, Women's and Children's Hospital, South Australia Health and Medical Research Institute, South Australia ImmunoGenomics Cancer Institute, University of Adelaide, Adelaide, Australia.ORCID 0000-0001-7733-383X
Dinisha GovenderDepartment of Oncology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0009-0005-6279-1770
Geoff B McCowageDepartment of Oncology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.ORCID 0000-0003-3471-8443
Ron FiresteinCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.ORCID 0000-0002-5255-1838
Meegan HowlettBrain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.ORCID 0000-0003-4332-6572
Raelene EndersbyBrain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.ORCID 0000-0003-3554-2769
Nicholas G GottardoBrain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.ORCID 0000-0002-1082-6776
Frank AlvaroPrecision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.ORCID 0000-0003-2828-8758
Sebastian M WaszakCentre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.ORCID 0000-0003-3042-9521
Martin R LarsenDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.ORCID 0000-0001-6203-0123
Yolanda Colino-SanguinoCancer Epigenetics Biology and Therapeutics, Precision Medicine Theme, Children's Cancer Institute, Sydney, New South Wales, Australia.ORCID 0000-0003-0128-5864
Fatima Valdes-MoraCancer Epigenetics Biology and Therapeutics, Precision Medicine Theme, Children's Cancer Institute, Sydney, New South Wales, Australia.ORCID 0000-0001-7490-0114
Andria RakotomalalaTumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, Lille, France.ORCID 0000-0002-6119-246X
Samuel MeignanTumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, Lille, France.ORCID 0000-0002-9386-7978
Eddy PasquierCentre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, Marseille, France.ORCID 0000-0003-2824-5002
Nicolas AndréCentre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, Marseille, France.ORCID 0000-0002-6786-4968
Esther HullemanPrincess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.ORCID 0000-0001-9256-947X
David D EisenstatChildren's Cancer Centre, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.ORCID 0000-0002-5976-0798
Nicholas A VitanzaBen Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington.ORCID 0000-0002-3966-4985
Javad NazarianCenter for Genetic Medicine Research, Children's National Hospital, Washington, DC.ORCID 0000-0002-1951-9828
Carl KoschmannDivision of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.ORCID 0000-0002-0825-7615
Sabine MuellerDepartment of Pediatrics, University Children's Hospital Zurich, Zurich, Switzerland.ORCID 0000-0002-3452-5150
Jason E CainCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.ORCID 0000-0003-3987-5894
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.ORCID 0000-0002-9063-5370
Funding
The role of ATRX mutation in the epigenetic dysregulation of cell cycle in pediatric high-grade gliomaR01NS119231 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KOSCHMANN, CARL J · 2021 to 2025
$1.9M
NINDS NIH HHS R01 NS119231
6 · The paper itself
Abstract
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. SIGNIFICANCE: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
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.
ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. · full record | OpenQuestion