DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency.
Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and in vivo tumorigenicity studies.
Hoey
Timothy
T
OncoMed Pharmaceuticals Inc., Redwood City, CA 94063, USA. timothy.hoey@oncomed.com
Yen
Wan-Ching
WC
Axelrod
Fumiko
F
Basi
Jesspreet
J
Donigian
Lucas
L
Dylla
Scott
S
Fitch-Bruhns
Maureen
M
Lazetic
Sasha
S
Park
In-Kyung
IK
Sato
Aaron
A
Satyal
Sanjeev
S
Wang
Xinhao
X
Clarke
Michael F
MF
Lewicki
John
J
Gurney
Austin
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018834:Chaperonin 60 / Q000819:agonists / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D000077146:Irinotecan; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D055502:Secondary Prevention; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D018834:Chaperonin 60; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D000077146:Irinotecan; D002166:Camptothecin