Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.
BACKGROUND
The Notch ligand Delta-like 4 (Dll4) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF) and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC).


RESULTS
Severe combined immunodeficiency (SCID) mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI) examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62%) that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54%) and ziv-aflibercept (46%). Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition), including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.


CONCLUSIONS
Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Kiersten Marie
KM
Miles
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
Mukund
M
Seshadri
Medicine and Experimental Oncology, University of Turin, Turin, Italy.
Eric
E
Ciamporcero
Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
Remi
R
Adelaiye
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
Bryan
B
Gillard
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
Paula
P
Sotomayor
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
Kristopher
K
Attwood
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Li
L
Shen
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Dylan
D
Conroy
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States of America.
Frank
F
Kuhnert
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States of America.
Alshad S
AS
Lalani
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States of America.
Gavin
G
Thurston
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
Roberto
R
Pili
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry*; D002135:Calcium-Binding Proteins; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D011758:Pyrroles / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015398:Signal Transduction; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; C000600154:enoticumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib