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

[severe combined immunodeficiency]

The Notch ligand Delta -like 4 (Dll 4 ) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis . Blockade of the Dll 4 -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 Dll 4 antibody , REGN 1035 , alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC ).Severe combined immunodeficiency (SCID ) mice bearing patient-derived clear cell RCC xenografts were treated with REGN 1035 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 REGN 1035 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 REGN 1035 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 REGN 1035 and ziv -aflibercept was also observed in a sunitinib resistant ccRCC model .Overall , these findings demonstrate the potent anti-tumor activity of Dll 4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll 4 and VEGF signaling pathways , highlighting the therapeutic potential of this treatment modality in RCC .