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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

Anti-tumor efficacy of anti-Dll4 (REGN1035) and anti-VEGF (ziv-aflibercept) in a sunitinib resistant RP-R-01 ccRCC patient-derived xenograft model.Mice with established subcutaneous tumors were treated with sunitinib for 4 weeks until tumor tissue was no longer responsive to treatment (tumor volume was ∼6 times that of pretreatment volume). At which time, mice were treated with either sunitinib, ziv-aflibercept, REGN1035 or the combination of ziv-aflibercept plus REGN1035 for a period of four weeks. (A) Tumor growth curve of average tumor volume (mm3) ± S.E. (B) End point tumor weights (g). *p<0.05, as compared to combination group using adjusted t-test analysis. Effect of REGN1035 and/or anti-VEGF (ziv-aflibercept) on sunitinib resistant RP-R-01 tumor vasculature. Sunitinib resistant tumors from treated mice were harvested, processed, and tissue sections were stained for the differential expression of CD31. (C) Representative pictures. (D) Blind quantitative analysis of CD31. Results are expressed as mean percentage positive stained area ± S.E. *p<0.05, as compared to combination group using t-test analysis.
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pone-0112371-g006: Anti-tumor efficacy of anti-Dll4 (REGN1035) and anti-VEGF (ziv-aflibercept) in a sunitinib resistant RP-R-01 ccRCC patient-derived xenograft model.Mice with established subcutaneous tumors were treated with sunitinib for 4 weeks until tumor tissue was no longer responsive to treatment (tumor volume was ∼6 times that of pretreatment volume). At which time, mice were treated with either sunitinib, ziv-aflibercept, REGN1035 or the combination of ziv-aflibercept plus REGN1035 for a period of four weeks. (A) Tumor growth curve of average tumor volume (mm3) ± S.E. (B) End point tumor weights (g). *p<0.05, as compared to combination group using adjusted t-test analysis. Effect of REGN1035 and/or anti-VEGF (ziv-aflibercept) on sunitinib resistant RP-R-01 tumor vasculature. Sunitinib resistant tumors from treated mice were harvested, processed, and tissue sections were stained for the differential expression of CD31. (C) Representative pictures. (D) Blind quantitative analysis of CD31. Results are expressed as mean percentage positive stained area ± S.E. *p<0.05, as compared to combination group using t-test analysis.

Mentions: To assess the anti-tumor efficacy of anti-Dll4 and anti-Dll4/VEGF combination therapy in a sunitinib resistant xenograft model, SCID mice were implanted subcutaneously with RP-R-01 tissue and treated with sunitinib until resistance was observed (when tumor size doubled that of pretreatment size). At which time, mice either continued to be treated with sunitinib or were switched to ziv-aflibercept, REGN1035 or the combination of ziv-aflibercept plus REGN1035. As shown in Figure 6A, only the combination of REGN1035 and ziv-aflibercept induced a significant tumor growth inhibition and even tumor regression, as compared to the group continued to be exposed to sunitinib. EOT tumor volume and weight are shown in Figures 6A and 6B, respectively: sunitinib (1010.5 mm3, 0.823 g), ziv-aflibercept (661.8 mm3, 0.600 g), REGN1035 (1075.3 mm3, 0.827 g), and combination (308.9 mm3, 0.311 g). The anti-tumor efficacy of the combination treated mice was found to be significantly different (p<0.05) from single agent sunitinib and REGN1035 treated mice, but not ziv-aflibercept treated mice. Interestingly, the greater anti-tumor effect in the combination group was not associated with greater inhibition of tumor blood vessel density (Fig. 6C–D). No overt signs of toxicity were observed, with only minimal weight loss was noted in the combination group (6.35%, ±1.28).


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)

Anti-tumor efficacy of anti-Dll4 (REGN1035) and anti-VEGF (ziv-aflibercept) in a sunitinib resistant RP-R-01 ccRCC patient-derived xenograft model.Mice with established subcutaneous tumors were treated with sunitinib for 4 weeks until tumor tissue was no longer responsive to treatment (tumor volume was ∼6 times that of pretreatment volume). At which time, mice were treated with either sunitinib, ziv-aflibercept, REGN1035 or the combination of ziv-aflibercept plus REGN1035 for a period of four weeks. (A) Tumor growth curve of average tumor volume (mm3) ± S.E. (B) End point tumor weights (g). *p<0.05, as compared to combination group using adjusted t-test analysis. Effect of REGN1035 and/or anti-VEGF (ziv-aflibercept) on sunitinib resistant RP-R-01 tumor vasculature. Sunitinib resistant tumors from treated mice were harvested, processed, and tissue sections were stained for the differential expression of CD31. (C) Representative pictures. (D) Blind quantitative analysis of CD31. Results are expressed as mean percentage positive stained area ± S.E. *p<0.05, as compared to combination group using t-test analysis.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112371-g006: Anti-tumor efficacy of anti-Dll4 (REGN1035) and anti-VEGF (ziv-aflibercept) in a sunitinib resistant RP-R-01 ccRCC patient-derived xenograft model.Mice with established subcutaneous tumors were treated with sunitinib for 4 weeks until tumor tissue was no longer responsive to treatment (tumor volume was ∼6 times that of pretreatment volume). At which time, mice were treated with either sunitinib, ziv-aflibercept, REGN1035 or the combination of ziv-aflibercept plus REGN1035 for a period of four weeks. (A) Tumor growth curve of average tumor volume (mm3) ± S.E. (B) End point tumor weights (g). *p<0.05, as compared to combination group using adjusted t-test analysis. Effect of REGN1035 and/or anti-VEGF (ziv-aflibercept) on sunitinib resistant RP-R-01 tumor vasculature. Sunitinib resistant tumors from treated mice were harvested, processed, and tissue sections were stained for the differential expression of CD31. (C) Representative pictures. (D) Blind quantitative analysis of CD31. Results are expressed as mean percentage positive stained area ± S.E. *p<0.05, as compared to combination group using t-test analysis.
Mentions: To assess the anti-tumor efficacy of anti-Dll4 and anti-Dll4/VEGF combination therapy in a sunitinib resistant xenograft model, SCID mice were implanted subcutaneously with RP-R-01 tissue and treated with sunitinib until resistance was observed (when tumor size doubled that of pretreatment size). At which time, mice either continued to be treated with sunitinib or were switched to ziv-aflibercept, REGN1035 or the combination of ziv-aflibercept plus REGN1035. As shown in Figure 6A, only the combination of REGN1035 and ziv-aflibercept induced a significant tumor growth inhibition and even tumor regression, as compared to the group continued to be exposed to sunitinib. EOT tumor volume and weight are shown in Figures 6A and 6B, respectively: sunitinib (1010.5 mm3, 0.823 g), ziv-aflibercept (661.8 mm3, 0.600 g), REGN1035 (1075.3 mm3, 0.827 g), and combination (308.9 mm3, 0.311 g). The anti-tumor efficacy of the combination treated mice was found to be significantly different (p<0.05) from single agent sunitinib and REGN1035 treated mice, but not ziv-aflibercept treated mice. Interestingly, the greater anti-tumor effect in the combination group was not associated with greater inhibition of tumor blood vessel density (Fig. 6C–D). No overt signs of toxicity were observed, with only minimal weight loss was noted in the combination group (6.35%, ±1.28).

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