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Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

1
School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland
2
The School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
*
Author to whom correspondence should be addressed.
Cells 2020, 9(6), 1503; https://doi.org/10.3390/cells9061503
Received: 7 May 2020 / Revised: 5 June 2020 / Accepted: 11 June 2020 / Published: 20 June 2020
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage. View Full-Text
Keywords: notch antibodies; gamma secretase inhibitors; cancer stem cells; drug resistance; clinical trial; breast tumours; lung tumours; leukaemias; desmoid tumours; adenoid cystic carcinoma notch antibodies; gamma secretase inhibitors; cancer stem cells; drug resistance; clinical trial; breast tumours; lung tumours; leukaemias; desmoid tumours; adenoid cystic carcinoma
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MDPI and ACS Style

Moore, G.; Annett, S.; McClements, L.; Robson, T. Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells 2020, 9, 1503.

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