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PLoS One. 2014 Nov 13;9(11):e112371. doi: 10.1371/journal.pone.0112371. eCollection 2014.

Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

Author information

1
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
2
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
3
Medicine and Experimental Oncology, University of Turin, Turin, Italy.
4
Department of Cancer Pathology & Prevention, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
5
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
6
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute Division, University at Buffalo, Buffalo, New York, United States of America.
7
Regeneron Pharmaceuticals, Inc., Tarrytown, New York, United States of America.
8
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.

Abstract

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).

METHODS AND 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.

PMID:
25393540
PMCID:
PMC4231048
DOI:
10.1371/journal.pone.0112371
[Indexed for MEDLINE]
Free PMC Article

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