Abstract
BackgroundThe 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 ResultsSevere 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.ConclusionsOverall, 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.
Highlights
Kidney cancer strikes close to 65,000 Americans every year and kills over 13,000 [1]
Xenograft models and treatment protocol RP-R-01 is a xenograft model established from a skin metastasis from a patient with sporadic ccRCC, previously treated with sunitinib
To assess the anti-tumor efficacy of anti-Delta-like 4 (Dll4) and anti-Dll4/ vascular endothelial growth factor (VEGF) combination therapy, Severe combined immunodeficiency (SCID) mice were implanted with RPR-01 or RP-R-02 ccRCC patient-derived xenograft tumors and treated with REGN1035 and/or sunitinib or ziv-aflibercept (Fig. 1A–C)
Summary
Kidney cancer strikes close to 65,000 Americans every year and kills over 13,000 [1]. Multi-targeted receptor TKI that is FDA approved for the treatment of RCC and GIST; and which has been shown to inhibit tumor vascularization by diminishing signaling through VEGF receptors 1 and 2, and platelet derived growth factor receptor (PDGFR). The clinical benefit associated with anti-VEGF therapies is often limited, as patients exhibit acquired tumor resistance to VEGF inhibition; there is great interest in identifying additional angiogenesis targets that, in combination with anti-VEGF therapies, can lead to more effective treatments for RCC. Given the cross-talk between the vascular endothelial growth factor (VEGF) and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a functionblocking Dll antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC)
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