Evidence map›Paper›PMID 33571541›Full record

ArticleCancer letters2021

TORC1/2 kinase inhibition depletes glutathione and synergizes with carboplatin to suppress the growth of MYC-driven medulloblastoma.

Rachael E Maynard, Brad Poore, Allison R Hanaford, Khoa Pham, Madison James, Jesse Alt, Youngran Park, Barbara S Slusher, Pablo Tamayo, Jill Mesirov and 4 more

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

Article in Cancer letters, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.8field-weighted citation impact, top 28% 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

6 citing papers in PubMed, 8 citations in OpenAlex.

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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

14 authors at 5 institutions in 2 countries.

Rachael E MaynardDivision of Pediatric Oncology, Department of Oncology, USA.
Brad PooreDivision of Pediatric Oncology, Department of Oncology, USA; Pathobiology Graduate Program, USA.
Allison R HanafordDivision of Pediatric Oncology, Department of Oncology, USA; Pathobiology Graduate Program, USA.
Khoa PhamDivision of Neuropathology, Department of Pathology, USA.
Madison JamesPathobiology Graduate Program, USA.
Jesse AltJohns Hopkins Drug Discovery, USA.
Youngran ParkDivision of Pediatric Oncology, Department of Oncology, USA.
Barbara S SlusherJohns Hopkins Drug Discovery, USA; Department of Neurology, USA.
Pablo TamayoMoores Cancer Center, University of California San Diego, La Jolla, CA, USA; Center for Novel Therapeutics, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Jill MesirovMoores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Tenley C ArcherEli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, MA, USA.
Scott L PomeroyEli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Cambridge, MA, USA.
Charles G EberhartDivision of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA.
Eric H RaabeDivision of Pediatric Oncology, Department of Oncology, USA; Division of Neuropathology, Department of Pathology, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, USA. Electronic address: eraabe2@jhmi.edu.
Broad Institute · USJohns Hopkins University · USMolecular Oncology (United States) · USUniversity of California San Diego · USDrug Discovery Laboratory (Norway) · NO

Funding

Translational Research Central ServicesP30CA006973 · NCI · JOHNS HOPKINS UNIVERSITY · PI WILLIAM George NELSON · 1985 to 2026
$208.6M
Using Networks to Seed Hierarchical Whole-cell Models of CancerU54CA209891 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI IDEKER, TREY, KROGAN, NEVAN J · 2017 to 2021
$10.9M
Supporting Integrative Genomic Analysis Users with GenePatternR01GM074024 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2005 to 2019
$6.6M
A Rational Systematic Approach to Find Combinations of Pharmacologic and Immune Therapies that Target Identifiable Oncogenic StatesU01CA217885 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI COHEN, EZRA, KAUFMAN, DAN S. · 2017 to 2021
$5.1M
Embryonal Brain Tumor NetworksU01CA184898 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI FRAENKEL, ERNEST, MESIROV, JILL P. · 2014 to 2019
$3.6M
Supporting and evolving Gene Set Enrichment Analysis and the Molecular Signatures Database for cancer researchU24CA220341 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P., TAMAYO, PABLO · 2018 to 2022
$3.4M
GenePattern Notebooks for Cancer ResearchU24CA194107 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2015 to 2019
$2.8M
NCI NIH HHS P30 CA006973NCI NIH HHS U01 CA184898NCI NIH HHS U01 CA217885NCI NIH HHS U24 CA194107NCI NIH HHS U24 CA220341NCI NIH HHS U54 CA209891NIGMS NIH HHS R01 GM074024
6 · The paper itself

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silico analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.

Indexed as

AnimalsAntineoplastic AgentsCarboplatinCell ProliferationCerebellar NeoplasmsFemaleGlutathioneHumansMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MedulloblastomaMiceProtein Kinase InhibitorsProto-Oncogene Proteins c-mycXenograft Model Antitumor AssaysAntineoplastic AgentsCarboplatinGlutathioneMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2Protein Kinase InhibitorsProto-Oncogene Proteins c-mycApoptosisINK128mTORPediatric brain tumorSapanisertib

Identifiers

PMID33571541
PMCPMC9195565
OpenAlexW3127318075

What OpenQuestion 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 OpenQuestion graph.