title: Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis.
abstract: BACKGROUND
  Dll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects.
  
  
  METHODS
  We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either Dll4 allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either Dll4 allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific Dll4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis.
  
  
  RESULTS
  Dll4 allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either Dll4 allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific Dll4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment.
  
  
  CONCLUSIONS
  Combination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone.
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, USA.
authors.forename: Dusan
authors.initials: D
authors.lastname: Djokovic
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
authors.forename: Joana
authors.initials: J
authors.lastname: Gigante
authors.forename: Marina
authors.initials: M
authors.lastname: Badenes
authors.forename: Lilliana
authors.initials: L
authors.lastname: Silva
authors.forename: Ren
authors.initials: R
authors.lastname: Liu
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Gong
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.forename: Antonio
authors.initials: A
authors.lastname: Duarte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002135:Calcium-Binding Proteins; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism*; D015316:Genetic Therapy; D007340:Insulinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D036224:Receptor, EphB4 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D047368:Tumor Burden
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D036388:Ephrin-B2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4