Evidence map›Paper›PMID 42493667›Full record

ArticleActa neuropathologica2026

Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.

Matthew Pun, Akash Deogharkar, Siva Kumar Natarajan, Nicholas Nuechterlein, Wentao Tian, Sunjong Ji, Eleanor Young, Fusheng Yang, Debra Hawes, Anthony C Andren and 15 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

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

25 authors.

Matthew Pun *Department of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA.
Akash Deogharkar *Department of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA.
Siva Kumar Natarajan *Department of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA.
Nicholas NuechterleinDepartment of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA.
Wentao TianDepartment of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA.
Sunjong JiDepartment of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA.
Eleanor YoungMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Fusheng YangDepartment of Pathology, Children's Hospital of Los Angeles, Los Angeles, CA, 90027, USA.
Debra HawesDepartment of Pathology, Children's Hospital of Los Angeles, Los Angeles, CA, 90027, USA.
Anthony C AndrenDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
John Henry OwenDepartment of Otolaryngology/Head Neck Surgery, University of Michigan School of Medicine, Ann Arbor, MI, 48109-5616, USA.
Sagar RauDepartment of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA.
Fengyun SuMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Xuhong CaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Abhijit ParoliaMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Mark PrinceDepartment of Otolaryngology/Head Neck Surgery, University of Michigan School of Medicine, Ann Arbor, MI, 48109-5616, USA.
Joshua FryDepartment of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Paul A GardnerDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Rendong YangDepartment of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Alexander R JudkinsDepartment of Pathology, Children's Hospital of Los Angeles, Los Angeles, CA, 90027, USA.
Carl J KoschmannDepartment of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA.
Andrew S VenteicherDepartment of Neurosurgery and Center for Skull Base and Pituitary Surgery, University of Minnesota, Minneapolis, MN, USA.
Costas A LyssiotisDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Arul M ChinnaiyanDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Sriram VennetiDepartment of Pathology, Laboratory of Brain Tumor Metabolism and Epigenetics, University of Michigan, Ann Arbor, MI, USA. svenneti@med.umich.edu.

Funding

Targeting integrated metabolic and epigenetic pathways in childhood ependymomasR01CA261926 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Deepak Nagrath, Benita Tamrazi · 2022 to 2026
$3.0M
Unravelling metabolic dependencies in H3K27M mutant DIPGR01NS110572 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sriram Venneti · 2019 to 2026
$2.7M
Targeting metabolic dependencies in ZFTA-RELA fusion childhood ependymomasR01NS127799 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sriram Venneti · 2023 to 2026
$1.8M
Investigating and targeting metabolic vulnerabilities in chordomaF31CA274989 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI PUN, MATTHEW JULIAN · 2022 to 2022
$30k
NCI NIH HHS F31 CA274989NCI NIH HHS R01 CA261926NINDS NIH HHS R01 NS110572NINDS NIH HHS R01 NS127799
6 · The paper itself

Abstract

Chordomas are rare cancers that arise along the axial skeleton. Alterations in metabolism are a hallmark of cancer, and we sought to identify metabolic vulnerabilities in chordoma. We discovered that the tricarboxylic acid (TCA)-related enzyme isocitrate dehydrogenase-1 (IDH1) was expressed highly in bulk and single-cell patient-derived chordomas and was associated with worse survival outcomes. IDH1 catalyzes the conversion of isocitrate and nicotinamide adenine dinucleotide phosphate (NADP+) to alpha-ketoglutarate (⍺-KG) and NADPH. This critical reaction influences TCA cycle metabolism, regulates epigenetic pathways, and affects redox balance. Both IDH1 knockdown and treatment with an inhibitor targeting IDH1 were toxic to chordoma cells. An integrated analysis of the transcriptomic, chromatin, and metabolomic responses on IDH1 inhibition converged on deregulated glutathione metabolism. IDH1 inhibition was associated with increased expression and enrichment of activating H3K27ac at NRF2 (nuclear factor erythroid 2-related factor 2) signature genes including those in the glutathione biosynthetic pathway. This was accompanied by reduction of both NADPH/NADP+ and reduced/oxidized glutathione (GSH/GSSG) ratios. Importantly, IDH1 inhibitor-driven toxicity was rescued via media supplementation with the antioxidant N-acetylcysteine, suggesting that IDH1 inhibition in chordomas creates a redox-dependent metabolic vulnerability. Finally, IDH1 inhibitor treatment reduced tumor growth in two independent chordoma mouse xenograft models. Our findings suggest a potential therapeutic avenue for further exploration in chordoma.

Indexed as

ChordomaIsocitrate DehydrogenaseAnimalsCell Line, TumorFemaleGlutathioneHumansMiceOxidation-ReductionGlutathioneIDH1 protein, humanIsocitrate DehydrogenaseChordomaIDH1MetabolismNRF2Redox

Identifiers

PMID42493667
PMCPMC13396039

What Socratic holds

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Registered trials

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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.