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The mTOR pathway as a therapeutic target for precision medicine

  • Patricia E. DillEmail author
  • Alexandre N. Datta
Leitthema

Abstract

The mTOR-pathway (mTOR: mammalian target of rapamycin) has been increasingly linked to the pathophysiology of epilepsy in recent years. As a master regulator of cell growth and survival, this signaling pathway has been associated with focal malformations of cortical development (MCD) subtypes often associated with intractable epilepsy. The tuberous sclerosis complex serves as a model disease, in which targeted therapy with mTOR inhibitors alleviate, improve, and might even reverse disease burden. Further, there is evidence of an mTOR effect on established antiepileptic strategies such as ketogenic diet and GABAergic-enhancing medication, which underlies the importance of the mTOR pathway in epileptogenesis.

Keywords

Signal pathways Epilepsy Tuberous sclerosis complex Focal cortical dysplasia Epileptogenesis 

Abbreviations

4E-BP1

Eukaryotic translation initiation factor 4E (elF4E)-binding protein 1

AE

Adverse events

AKT

Protein kinase B

AML

Angiomyolipoma

ATG13

Autophagy-related protein 13

CBD

Cannabidiol

FCD

Focal cortical dysplasia

GABA

γ-Aminobutyric acid

GDP

Guanosine diphosphate

GFAP

Glial fibrillary acidic protein

GLAST

Glutamate aspartate transporter 1

GLT-1

Glutamate transporter 1

GTP

Guanosine-5′-triphosphate

HD

High-dose

KD

Ketogenic diet

LD

Low-dose

MCD

Malformation of cortical development

mTOR

Mammalian target of rapamycin

mTORC1

mTOR complex 1

mTORC2

mTOR complex 2

mTORi

mTOR inhibitors

PDK1

Phosphoinositide-dependent kinase-1

PI3K

Phosphoinositide 3‑kinase

Rheb

RAS homolog enriched in brain

S6K1

70-kDa Ribosomal protein S6 kinase 1

SEGA

Giant cell astrocytoma

ULK1

Unc-51-like autophagy activating kinase 1

VGB

Vigabatrin

Der mTOR-Signalweg als therapeutisches Target für die Präzisionsmedizin

Zusammenfassung

Der mTOR-Signalweg (mTOR: „mammalian target of rapamycin“) wird in den letzten Jahren zunehmend mit der Pathophysiologie der Epilepsie in Zusammenhang gebracht. Als einer der Hauptschnittpunkte in der Regulation von Zellwachstum und Überleben ist dieser Signalweg mit Subtypen fokaler Malformationen der kortikalen Entwicklung (MCD) vergesellschaftet, welche oft mit therapieresistenter Epilepsie einhergehen. Die tuberöse Sklerose dient hier als Modellerkrankung, bei welcher mit dem gezielten Einsatz von mTOR-Inhibitoren die Krankheitslast gelindert oder gar rückgängig gemacht werden kann. Darüber hinaus gibt es zunehmend Hinweise für einen mTOR-Effekt auf bereits etablierte antiepileptische Therapien wie ketogene Diät und GABAerg wirkende Substanzen, was die Wichtigkeit des mTOR-Signalwegs in der Epileptogenese unterstreicht.

Schlüsselwörter

Signalwege Epilepsie Tuberöse Sklerose Fokale kortikale Dysplasie Epileptogenese 

Notes

Compliance with ethical guidelines

Conflict of interest

P.E. Dill reports research grants, speaker honoraria and personal fees for advisory boards from Novartis. A.N. Datta has consultancy contracts with Idorsia Pharmaceuticals Ltd and F.Hoffmann-La Roche AG

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.

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Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatric Neurology and Developmental MedicineUniversity of Basel Children’s HospitalBaselSwitzerland

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