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

Kiersten Marie Miles; Mukund Seshadri; Eric Ciamporcero; Remi Adelaiye; Bryan Gillard; Paula Sotomayor; Kristopher Attwood; Li Shen; Dylan Conroy; Frank Kuhnert; Alshad S. Lalani; Gavin Thurston; Roberto Pili

doi:10.1371/journal.pone.0112371

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

Kiersten Marie Miles, Mukund Seshadri, Eric Ciamporcero, Remi Adelaiye, Bryan Gillard, Paula Sotomayor, Kristopher Attwood, Li Shen, Dylan Conroy, Frank Kuhnert, Alshad S. Lalani, Gavin Thurston, Roberto Pili

Medicine School

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

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 functionblocking 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.

Original language	English
Article number	e112371
Journal	PLoS ONE
Volume	9
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0112371
Publication status	Published - 13 Nov 2014

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology
General Agricultural and Biological Sciences
General

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Miles, K. M., Seshadri, M., Ciamporcero, E., Adelaiye, R., Gillard, B., Sotomayor, P., Attwood, K., Shen, L., Conroy, D., Kuhnert, F., Lalani, A. S., Thurston, G., & Pili, R. (2014). Dll4 blockade potentiates the anti-tumor Effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts. PLoS ONE, 9(11), Article e112371. https://doi.org/10.1371/journal.pone.0112371

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title = "Dll4 blockade potentiates the anti-tumor Effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts",

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 functionblocking 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.",

author = "Miles, {Kiersten Marie} and Mukund Seshadri and Eric Ciamporcero and Remi Adelaiye and Bryan Gillard and Paula Sotomayor and Kristopher Attwood and Li Shen and Dylan Conroy and Frank Kuhnert and Lalani, {Alshad S.} and Gavin Thurston and Roberto Pili",

note = "Publisher Copyright: {\textcopyright} 2014 Miles et al.",

year = "2014",

month = nov,

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doi = "10.1371/journal.pone.0112371",

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T1 - Dll4 blockade potentiates the anti-tumor Effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts

AU - Miles, Kiersten Marie

AU - Seshadri, Mukund

AU - Ciamporcero, Eric

AU - Adelaiye, Remi

AU - Gillard, Bryan

AU - Sotomayor, Paula

AU - Attwood, Kristopher

AU - Shen, Li

AU - Conroy, Dylan

AU - Kuhnert, Frank

AU - Lalani, Alshad S.

AU - Thurston, Gavin

AU - Pili, Roberto

PY - 2014/11/13

Y1 - 2014/11/13

N2 - 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 functionblocking 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.

AB - 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 functionblocking 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.

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

Abstract

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