Key Points
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Notch signalling has key roles in the development and homeostasis of most organs, including — notably — the haematopoietic system, skin, vascular system and liver.
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An increasing number of known human diseases relate to dysregulated Notch signalling, including developmental congenital disorders and cancers with de novo NOTCH mutations.
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The core pathway is simple but provides ample potential therapeutic possibilities. Viable targets include inhibition of receptor cleavage by γ-secretase inhibitors and blockade of specific receptors or ligands with antibodies.
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Crosstalk between Notch and other signalling mechanisms may provide possibilities for combinatorial treatments, especially in cancer where targeting several pathways simultaneously may offer considerable benefits. Numerous clinical trials are underway with the aim of modulating Notch signalling.
Abstract
The Notch signalling pathway is evolutionarily conserved and is crucial for the development and homeostasis of most tissues. Deregulated Notch signalling leads to various diseases, such as T cell leukaemia, Alagille syndrome and a stroke and dementia syndrome known as CADASIL, and so strategies to therapeutically modulate Notch signalling are of interest. Clinical trials of Notch pathway inhibitors in patients with solid tumours have been reported, and several approaches are under preclinical evaluation. In this Review, we focus on aspects of the pathway that are amenable to therapeutic intervention, diseases that could be targeted and the various Notch pathway modulation strategies that are currently being explored.
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Acknowledgements
E.R.A. holds a junior research grant from the Swedish Research Council. Work in U.L.'s laboratory is funded by the Swedish Research Council (DBRM, StratRegen and project grant), the Swedish Cancer Society, Knut och Alice Wallenbergs Stiftelse and Karolinska Institutet (the Breast Cancer Theme Center (BRECT) and a Distinguished Professor Award).
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Supplementary information
Supplementary information S1 (table)
Ongoing and completed studies with Notch targeting (from clinicaltrials.gov), same as Table 3, but including stated purpose of trial. (PDF 231 kb)
Glossary
- Signal-sending cell
-
The cell on which the ligand is expressed. Canonical Notch signalling is seen as a uni-directional signalling pathway in which the ligand is expressed on one cell, which 'sends' the signal, and the receptor is expressed on a contacting cell, which 'receives' the signal.
- Signal-receiving cell
-
The cell on which the receptor is expressed. Canonical Notch signalling is seen as a uni-directional signalling pathway in which the ligand is expressed on one cell, which 'sends' the signal, and the receptor is expressed on a contacting cell, which 'receives' the signal.
- Epithelial to mesenchymal transition
-
(EMT). A phenotypic change in cells where they lose epithelial and/or adhesive properties and become more motile. This is often associated with the onset of cancer metastasis.
- Wolff–Parkinson–White syndrome
-
A heart condition in which aberrant conductance between atria and ventricles leads to an increased heart rate.
- Maximum tolerated dose
-
The highest dose of a treatment that will produce the desired effect without causing unacceptable toxicity.
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Andersson, E., Lendahl, U. Therapeutic modulation of Notch signalling — are we there yet?. Nat Rev Drug Discov 13, 357–378 (2014). https://doi.org/10.1038/nrd4252
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DOI: https://doi.org/10.1038/nrd4252
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