Evidence map›Paper›PMID 32144278›Full record

ArticleScientific reports2020

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma.

Jessica E Sagers, Roberta L Beauchamp, Yanling Zhang, Sasa Vasilijic, Limeng Wu, Patrick DeSouza, Richard Seist, Wenjianlong Zhou, Lei Xu, Vijaya Ramesh and 1 more

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

Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed, 2 pooled it
1.8field-weighted citation impact, top 12% 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

25 citing papers in PubMed, 2 syntheses or guidelines pooled it, 34 citations in OpenAlex.

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  19. Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2.Molecular therapy. Methods & clinical development · 2022
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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

11 authors at 2 institutions in 2 countries.

Jessica E Sagers *Eaton-Peabody Laboratories and Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA.
Roberta L Beauchamp *Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Yanling ZhangEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Sasa VasilijicEaton-Peabody Laboratories and Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA.
Limeng WuEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Patrick DeSouzaCenter for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Richard SeistEaton-Peabody Laboratories and Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA.
Wenjianlong ZhouEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Lei XuEdwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. lei@steele.mgh.havard.edu.ORCID http://orcid.org/0000-0003-0525-183X
Vijaya RameshCenter for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. ramesh@helix.mgh.harvard.edu.
Konstantina M StankovicEaton-Peabody Laboratories and Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA. konstantina_stankovic@meei.harvard.edu.
Harvard University · USMassachusetts Eye and Ear Infirmary · US

Funding

Mechanisms of sensorineural hearing loss: secreted factorsR01DC015824 · NIDCD · STANFORD UNIVERSITY · PI STANKOVIC, KONSTANTINA M · 2016 to 2020
$2.2M
NIDCD NIH HHS R01 DC015824
6 · The paper itself

Abstract

Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral vestibular schwannomas (VS) that arise from neoplastic Schwann cells (SCs). NF2-associated VSs are often accompanied by meningioma (MN), and the majority of NF2 patients show loss of the NF2 tumor suppressor. mTORC1 and mTORC2-specific serum/glucocorticoid-regulated kinase 1 (SGK1) are constitutively activated in MN with loss of NF2. In a recent high-throughput kinome screen in NF2-null human arachnoidal and meningioma cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation. Subsequently, we demonstrated in vitro and in vivo efficacy of combination therapy with the dual mTORC1/2 inhibitor AZD2014 and the multi-kinase inhibitor dasatinib. For these reasons, we investigated activated mTORC1/2 and EPH receptor-mediated signaling in sporadic and NF2-associated VS. Using primary human VS cells and a mouse allograft model of schwannoma, we evaluated the dual mTORC1/2 inhibitor AZD2014 and the tyrosine kinase inhibitor dasatinib as monotherapies and in combination. Escalating dose-response experiments on primary VS cells grown from 15 human tumors show that combination therapy with AZD2014 and dasatinib is more effective at reducing metabolic activity than either drug alone and exhibits a therapeutic effect at a physiologically reasonable concentration (~0.1 µM). In vivo, while AZD2014 and dasatinib each inhibit tumor growth alone, the effect of combination therapy exceeds that of either drug. Co-targeting the mTOR and EPH receptor pathways with these or similar compounds may constitute a novel therapeutic strategy for VS, a condition for which there is no FDA-approved pharmacotherapy.

Indexed as

Disease Models, AnimalAnimalsBenzamidesDasatinibDrug Therapy, CombinationFemaleHumansMaleMiceMice, Inbred C57BLMice, KnockoutMorpholinesNeurofibromin 2Neuroma, AcousticProtein Kinase InhibitorsPyrimidinesBenzamidesDasatinibMorpholinesMTOR protein, humanNeurofibromin 2NF2 protein, humanNf2 protein, mouseProtein Kinase InhibitorsPyrimidinesReceptor, EphA1TOR Serine-Threonine Kinasesvistusertib

Identifiers

PMID32144278
PMCPMC7060236
OpenAlexW3009851500

What OpenQuestion holds

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LicenceCC BY
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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.