Evidence map›Paper›PMID 31398252›Full record

ArticleNeuro-oncology2020

Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas.

Han Shen, Man Yu, Maria Tsoli, Cecilia Chang, Swapna Joshi, Jie Liu, Scott Ryall, Yevgen Chornenkyy, Robert Siddaway, Cynthia Hawkins and 1 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed, 1 pooled it
2.7field-weighted citation impact, top 9% of its field
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

52 citing papers in PubMed, 1 synthesis or guideline pooled it, 68 citations in OpenAlex.

  1. Pooled it
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  17. Brain development and bioenergetic changes.Neurobiology of disease · 2024
    Review
  18. Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts.Pharmaceuticals (Basel, Switzerland) · 2024
    Review
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  20. Article
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

11 authors at 2 institutions in 2 countries.

Han ShenChildren's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Man YuThe Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Maria TsoliChildren's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Cecilia ChangChildren's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Swapna JoshiChildren's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Jie LiuChildren's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Scott RyallThe Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Yevgen ChornenkyyThe Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Robert SiddawayThe Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Cynthia HawkinsThe Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
David S ZieglerChildren's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
UNSW Sydney · AUUniversity of Toronto · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundDespite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs.

methodsMitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts.

resultsAverage mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate-activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo.

conclusionsOur results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.

Indexed as

Aminoimidazole CarboxamideAnimalsBrain NeoplasmsChildDichloroacetic AcidDNA, MitochondrialEnergy MetabolismGene DosageGliomaGlycolysisHumansMiceRibonucleotidesXenograft Model Antitumor AssaysAICA ribonucleotideAminoimidazole CarboxamideDichloroacetic AcidDNA, MitochondrialRibonucleotidesDIPGgliomasmitochondriaradiotherapy

Identifiers

PMID31398252
PMCPMC6954438
OpenAlexW2967570386

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

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.