Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer

Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and cross-talk with other signaling pathways. The canonical Notch p...

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Bibliographic Details
Published in:Clinical cancer research 2015-03, Vol.21 (5), p.955-961
Main Authors: Previs, Rebecca A, Coleman, Robert L, Harris, Adrian L, Sood, Anil K
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Drug Discovery
Humans
Molecular Targeted Therapy
Neoplasms - drug therapy
Neoplasms - metabolism
Oncogene Proteins - metabolism
Patient Selection
Receptors, Notch - antagonists & inhibitors
Receptors, Notch - metabolism
Signal Transduction - drug effects
Translational Research, Biomedical
Tumor Suppressor Proteins - metabolism
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Summary:Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and cross-talk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3-4, Jagged 1-2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Because the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA-approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK-0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-14-0809