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Notch/DLL4
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Notch DLL4(3)
The Notch signaling pathway is a critical component of cardiovascular formation and is required for the selection of endothelial tip and stalk cells during sprouting angiogenesis.(1, 2) The notch signaling pathway is important for cell-cell communication, endocrine development, angiogenesis.(1,4) Activation of Notch takes place primarily in connector cells and cells that line patent stable blood vessels through direct interaction with the Notch ligand, Dll4, which is expressed in the endothelial tip cells. VEGF signaling can be downregulated by Notch and VEGF is able to induce DLL4 expression.(1) Thus the DLL4/Notch pathway can be considered a negative feedback system of the VGFR pathway.(10)
Notch signaling also has a role in the following processes: The Notch pathway is made up of four transmembrane receptors (Notch1-4) and five transmembrane ligands DLL 1, 3, and 4, and Jagged 1 and 2.(3) Binding of the TACE ligand promotes two proteolytic processing events; as a result of proteolysis, the intracellular domain is liberated and can enter the nucleus to engage other DNA-binding proteins and regulate gene expression.(1,8)
The notch ligands are single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In mammals, the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-like and Jagged ligands, as well as possibly a variety of other ligands, such as F3/contactin. Notch has four different notch receptors: NOTCH1, NOTCH2, NOTCH3, and NOTCH4. Dll4 is a protein encoded by the DLL4 gene. The delta gene family encodes Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain.(9) DLL1, DLL3, DLL4, Jagged1, and Jagged2 bind to Notch receptor as ligands. Among these ligands, DLL4 has been the most intensely investigated in the area of tumor angiogenesis, because DLL4 is strongly expressed in tumor vascular endothelial cells but more weakly in normal vascular endothelial cells.(10)
For arterial specification, VEGF induces expression of Notch signaling genes, including Notch1 and its ligand, Dll4, and Foxc1 and Foxc2 transcription factors directly regulate Dll4 expression.(11) Dll4 ligand signaling is a pathway in angiogenic sprouting and acts as a negative regulator of this process induced by VEGF.(12-14) Forkhead transcription factor Foxc2 directly regulates expression of various genes involved in angiogenesis, CXCR4, INT?3, Dll4, and Ang-2, thereby controlling angiogenic processes. Thus, Foxc2 is now recognized as a novel regulator of vascular formation and remodeling.(12) In mammals there are three Fringe GlcNAc-transferases, named lunatic fringe, manic fringe, and radical fringe. These enzymes are responsible for a fringe effect on notch signaling. If Fringe adds a GlcNAc to the O-fucose sugar then the subsequent addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, notch signals strongly when it interacts with the DLL, but has markedly inhibited signaling when interacting with the Jagged ligand.(1)
Notch signaling is disregulated in many cancers, and faulty notch signaling is implicated in T-ALL.(1, 15, 16) Notch signaling plays a major role in normal breast development and has been implicated in cancer initiation and progression.(3) Targeting Notch signaling as a treatment for BC is promising, but the pathway is active in other tissues.(3)

Drugs/Indications
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
demcizumab OMP-21M18   OncoMed P2: PC; P1/2: peritoneal; P1: CRC, solid trials
  PF-03084014   Pfizer P2: pancreatic, BC, Kaposi; P1: various trials
  RG4733 RO4929097  Roche P2: solid, NSCLC, BC, GBM, RCC, melanoma, NSCLC, CRC; P1/2: rhabdoid, astrocytoma; P1: various trials
  VB-111 GT-111   Vascular P2: GBM, thyroid, RCC, NET, ovarian; P1: solid trials
M402 M-ONC 402 Momenta P1/2: pancreatic trials
MK-0752  c7617  Merck P1/2: BC, PC; P1: solid, brain, CNS, pancreatic, leukemia, lymphoma trials
OMP-59R5 MorphSys P1/2: pancreatic, SCLC, solid trials
enoticumab REGN421  SAR153192 Regeneron P1: solid trials
BMS-906024 BMS P1: solid, lymphoblastic leukemia trials
BMS-986115 BMS P1: solid trials
LY3039478 Eli Lilly P1: various trials
MEDI-0639 MedImmune P1: solid trials
OMP-52M51 OncoMed P1: lymphoma, solid trials
PF-06650808 Pfizer P1: solid, BC trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
angiostatin Bolder Last new trial started in 2003; P2: NSCLC; P1/2: solid trials


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References

1. Hüttemann M PP, Rainbolt M, Sanderson TH, Kagan VE, Samavati L, Doan JW, Lee I. The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: From respiration to apoptosis. Mitochondrion. 2011;11(3):369-81. PMCID: 21296189.

2. Kume T. Ligand-dependent Notch signaling in vascular formation. Notch Signaling in Embryology and Cancer: Springer; 2012. p. 210-22.

3. Harrison H FG, Brennan KR, Clarke RB. Breast cancer stem cells: something out of notching? Cancer Res. 2010;70(22):8973-6. PMCID: 21045140.

4. Hellström M, Phng L-K, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445(7129):776-80.

5. Williams CK, Li J-L, Murga M, Harris AL, Tosato G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood. 2006;107(3):931-9.

6. Liu Z-J, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Molecular and cellular biology. 2003;23(1):14-25.

7. Kim PG, Albacker CE, Lu Y-f, Jang I-h, Lim Y, Heffner GC, et al. Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition. Proceedings of the National Academy of Sciences. 2013;110(2):E141-E50.

8. Alatrash G MJ. Vaccines as consolidation therapy for myeloid leukemia. Expert Rev Hematol. 2011;4(1):37-50. PMCID: 21322777.

9. Ghosh JC, Dohi, T., Kang, B. H. and Altieri, D. C. Hsp60 regulation of tumor cell apoptosis. J Biol Chem. 2008;283:5188-94.

10. Ichihara E KK, Tanimoto M. Targeting angiogenesis in cancer therapy. Acta Med Okayama. 2011;65(6):353-62. PMCID: 22189475.

11. T K. Specification of arterial, venous, and lymphatic endothelial cells during embryonic development. Histol Histopathol. 2010;25(5):637-46. PMCID: 20238301.

12. T K. Foxc2 transcription factor: a newly described regulator of angiogenesis. Trends Cardiovasc Med. 2008;18(6):224-8. PMCID: 19185813.

13. RS K. Tumor angiogenesis. N Engl J Med. 2008;358:2039-49. PMCID: 18463380.

14. Siekmann AF CL, Lawson ND. Modulation of VEGF signalling output by the Notch pathway. Bioessays. 2008;30:303-13. PMCID: 18348190.

15. Sharma VM, Draheim KM, Kelliher MA. The Notch1/c-Myc pathway in T cell leukemia. Cell Cycle. 2007;6(8):927-30.

16. Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, et al. Direct inhibition of the NOTCH transcription factor complex. Nature. 2009;462(7270):182-8.