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 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.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Rebecca A
RA
Previs
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Robert L
RL
Coleman
The Weatherall Institute of Molecular Medicine, The University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Adrian L
AL
Harris
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Center for RNA Interference and Non-Coding RNA, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. asood@mdanderson.org.
Anil K
AK
Sood
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D055808:Drug Discovery; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D018579:Patient Selection; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D015513:Oncogene Proteins; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins