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

Miles KM, Seshadri M, Ciamporcero E, Adelaiye R, Gillard B, Sotomayor P, Attwood K, Shen L, Conroy D, Kuhnert F, Lalani AS, Thurston G, Pili R - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genitourinary Program, Roswell Park Cancer Institute, 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.

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Related in: MedlinePlus

Effect of REGN1035 and/or anti-VEGF (sunitinib or ziv-aflibercept) treatment on tumor cell viability.Mice (8 mice/group) implanted with (A, B) RP-R-01 or (C) RP-R-02 tissues were treated with vehicle, sunitinib, or ziv-aflibercept and/or REGN1035. Tumors were harvested, processed, and tissue sections were stained for hematoxylin and eosin. Left panels: Representative images of tumor necrosis. (D, E, F) Quantitative analysis was done in a blinded fashion. Results are expressed as mean percentage necrotic area ± S.E. *p<0.05 using adjusted t-test analysis.
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pone-0112371-g002: Effect of REGN1035 and/or anti-VEGF (sunitinib or ziv-aflibercept) treatment on tumor cell viability.Mice (8 mice/group) implanted with (A, B) RP-R-01 or (C) RP-R-02 tissues were treated with vehicle, sunitinib, or ziv-aflibercept and/or REGN1035. Tumors were harvested, processed, and tissue sections were stained for hematoxylin and eosin. Left panels: Representative images of tumor necrosis. (D, E, F) Quantitative analysis was done in a blinded fashion. Results are expressed as mean percentage necrotic area ± S.E. *p<0.05 using adjusted t-test analysis.

Mentions: To examine the effects of treatment on tumor necrosis, end of treatment tumor tissue sections were stained with hematoxylin and eosin (H&E). As shown in Figures 2A–C, a modest reduction in viable tissue was observed following single agent treatment with anti-VEGF therapy (sunitinib, 3–21% necrosis), (ziv-aflibercept, 9% necrosis). Tumors treated with REGN1035 or combinations displayed a substantially increased percentage of necrosis than vehicle or VEGF inhibitor-treated tumors (vehicle, 7–11%; REGN1035, 44–52%; REGN1035 plus sunitinib, 41–57%; REGN1035 plus ziv-aflibercept, 86%, all p<0.05 vs. vehicle) (Fig. 2D–F).


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

Miles KM, Seshadri M, Ciamporcero E, Adelaiye R, Gillard B, Sotomayor P, Attwood K, Shen L, Conroy D, Kuhnert F, Lalani AS, Thurston G, Pili R - PLoS ONE (2014)

Effect of REGN1035 and/or anti-VEGF (sunitinib or ziv-aflibercept) treatment on tumor cell viability.Mice (8 mice/group) implanted with (A, B) RP-R-01 or (C) RP-R-02 tissues were treated with vehicle, sunitinib, or ziv-aflibercept and/or REGN1035. Tumors were harvested, processed, and tissue sections were stained for hematoxylin and eosin. Left panels: Representative images of tumor necrosis. (D, E, F) Quantitative analysis was done in a blinded fashion. Results are expressed as mean percentage necrotic area ± S.E. *p<0.05 using adjusted t-test analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231048&req=5

pone-0112371-g002: Effect of REGN1035 and/or anti-VEGF (sunitinib or ziv-aflibercept) treatment on tumor cell viability.Mice (8 mice/group) implanted with (A, B) RP-R-01 or (C) RP-R-02 tissues were treated with vehicle, sunitinib, or ziv-aflibercept and/or REGN1035. Tumors were harvested, processed, and tissue sections were stained for hematoxylin and eosin. Left panels: Representative images of tumor necrosis. (D, E, F) Quantitative analysis was done in a blinded fashion. Results are expressed as mean percentage necrotic area ± S.E. *p<0.05 using adjusted t-test analysis.
Mentions: To examine the effects of treatment on tumor necrosis, end of treatment tumor tissue sections were stained with hematoxylin and eosin (H&E). As shown in Figures 2A–C, a modest reduction in viable tissue was observed following single agent treatment with anti-VEGF therapy (sunitinib, 3–21% necrosis), (ziv-aflibercept, 9% necrosis). Tumors treated with REGN1035 or combinations displayed a substantially increased percentage of necrosis than vehicle or VEGF inhibitor-treated tumors (vehicle, 7–11%; REGN1035, 44–52%; REGN1035 plus sunitinib, 41–57%; REGN1035 plus ziv-aflibercept, 86%, all p<0.05 vs. vehicle) (Fig. 2D–F).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genitourinary Program, Roswell Park Cancer Institute, 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.

Show MeSH
Related in: MedlinePlus