title: Anti-DLL4 has broad spectrum activity in pancreatic cancer dependent on targeting DLL4-Notch signaling in both tumor and vasculature cells.
abstract: OBJECTIVE
  We previously showed that targeting Delta-like ligand 4 (DLL4) in colon and breast tumors inhibited tumor growth and reduced tumor initiating cell frequency. In this report, we have extended these studies to pancreatic cancer and probed the mechanism of action in tumor and stromal cells involved in antitumor efficacy.
  
  
  METHODS
  Patient-derived pancreatic xenograft tumor models were used to evaluate the antitumor effect of anti-DLL4. To investigate the mechanism of action, we compared the activity of targeting DLL4 in tumor cells with an anti-human DLL4 antibody (anti-hDLL4) and in the host stroma/vasculature with an anti-mouse DLL4 antibody (anti-mDLL4). The effect of these antibodies on cancer stem cell frequency was examined by in vivo limiting dilution assays.
  
  
  RESULTS
  The combination of anti-hDLL4 and anti-mDLL4 was efficacious in a broad spectrum of pancreatic tumor xenografts and showed additive antitumor activity together with gemcitabine. Treatment with either anti-hDLL4 or anti-mDLL4 delayed pancreatic tumor recurrence following termination of gemcitabine treatment, and the two together produced an additive effect. Anti-hDLL4 had a pronounced effect in reducing the tumorigenicity of pancreatic cancer cells based on serial transplantation and tumorsphere assays. In contrast, disruption of tumor angiogenesis with anti-mDLL4 alone or with anti-VEGF had minimal effects on tumorigenicity. Gene expression analyses indicated that anti-DLL4 treatment regulated genes that participate in Notch signaling, pancreatic differentiation, and epithelial-to-mesenchymal transition.
  
  
  CONCLUSIONS
  Our findings suggest a novel therapeutic approach for pancreatic cancer treatment through antagonism of DLL4/Notch signaling.
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, CA, USA.
authors.forename: Wan-Ching
authors.initials: WC
authors.lastname: Yen
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Fischer
authors.forename: Mark
authors.initials: M
authors.lastname: Hynes
authors.forename: Jingjiang
authors.initials: J
authors.lastname: Wu
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.forename: Lucia
authors.initials: L
authors.lastname: Beviglia
authors.forename: V Pete
authors.initials: VP
authors.lastname: Yeung
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Song
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: John
authors.initials: J
authors.lastname: Lewicki
authors.forename: Austin
authors.initials: A
authors.lastname: Gurney
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.forename: Timothy
authors.initials: T
authors.lastname: Hoey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage*; D002135:Calcium-Binding Proteins; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051880:Receptors, Notch / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000888:Antibodies, Anti-Idiotypic; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000093542:Gemcitabine