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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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Vascular response of RP-R-01 tumors to combined DLL4-VEGF blockade.MRI-based estimates of relative blood volume estimates of RP-R-01 tumors at (A) 24 hours and (B) 2 weeks (C) Panel of images represent contrast enhancement maps of a representative tumor from each group 2 weeks post treatment. Three contiguous slices of the tumor are shown. All treatment groups showed significant reduction in rBV compared to controls. Combination treatment resulted in the greatest reduction in tumor perfusion. *p<0.05, **p<0.01, ***p<0.001.
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pone-0112371-g005: Vascular response of RP-R-01 tumors to combined DLL4-VEGF blockade.MRI-based estimates of relative blood volume estimates of RP-R-01 tumors at (A) 24 hours and (B) 2 weeks (C) Panel of images represent contrast enhancement maps of a representative tumor from each group 2 weeks post treatment. Three contiguous slices of the tumor are shown. All treatment groups showed significant reduction in rBV compared to controls. Combination treatment resulted in the greatest reduction in tumor perfusion. *p<0.05, **p<0.01, ***p<0.001.

Mentions: Next, we examined the effects of combined Dll4 and VEGF blockade on tumor vascular function using contrast-enhanced MRI. Tumors were imaged at 24 hours (early) and 2 weeks (late) after the start of treatment to characterize the vascular response of tumors to acute and chronic administration of both agents. Quantitative estimates of contrast agent concentration (ΔR1) in tumors (n = 3 per group) and contralateral kidneys were obtained to compute changes in blood volume (Y-intercept) and permeability (slope). At 24 hours post treatment (Fig. 5A), a significant reduction in blood volume (p<0.001) in tumors treated with ziv-aflibercept alone (0.25±0.06) or REGN1035 alone (0.72±0.10) compared to control tumors (1.08±0.09) was observed. Animals treated with the combination showed the greatest reduction in vascular volume compared to controls and either monotherapy (p<0.0001). Combination treatment resulted in durable anti-vascular activity with a significant (p<0.0001) reduction in blood volume (0.015±0.06) at the two week time point (Fig. 5B) compared to controls (0.75±0.05), ziv-aflibercept alone (0.14±0.06) and REGN1035 alone (0.20±0.04). No difference in perfusion (ΔR1) of kidneys was observed with single agent or combination treatments at both time points (Fig. S2). The panel of images shown in Figure 5C represent contrast enhancement maps of three contiguous slices of a tumor in each group at the end of two week treatment period. While single agent treatments resulted in reduction in perfusion compared to control tumors, combination treatment resulted in marked reduction in tumor growth and perfusion as evidenced by decreased contrast agent uptake in the tumor. Corresponding 3D MR angiography images of a representative tumor in all 4 groups is shown in Figure S3.


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)

Vascular response of RP-R-01 tumors to combined DLL4-VEGF blockade.MRI-based estimates of relative blood volume estimates of RP-R-01 tumors at (A) 24 hours and (B) 2 weeks (C) Panel of images represent contrast enhancement maps of a representative tumor from each group 2 weeks post treatment. Three contiguous slices of the tumor are shown. All treatment groups showed significant reduction in rBV compared to controls. Combination treatment resulted in the greatest reduction in tumor perfusion. *p<0.05, **p<0.01, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112371-g005: Vascular response of RP-R-01 tumors to combined DLL4-VEGF blockade.MRI-based estimates of relative blood volume estimates of RP-R-01 tumors at (A) 24 hours and (B) 2 weeks (C) Panel of images represent contrast enhancement maps of a representative tumor from each group 2 weeks post treatment. Three contiguous slices of the tumor are shown. All treatment groups showed significant reduction in rBV compared to controls. Combination treatment resulted in the greatest reduction in tumor perfusion. *p<0.05, **p<0.01, ***p<0.001.
Mentions: Next, we examined the effects of combined Dll4 and VEGF blockade on tumor vascular function using contrast-enhanced MRI. Tumors were imaged at 24 hours (early) and 2 weeks (late) after the start of treatment to characterize the vascular response of tumors to acute and chronic administration of both agents. Quantitative estimates of contrast agent concentration (ΔR1) in tumors (n = 3 per group) and contralateral kidneys were obtained to compute changes in blood volume (Y-intercept) and permeability (slope). At 24 hours post treatment (Fig. 5A), a significant reduction in blood volume (p<0.001) in tumors treated with ziv-aflibercept alone (0.25±0.06) or REGN1035 alone (0.72±0.10) compared to control tumors (1.08±0.09) was observed. Animals treated with the combination showed the greatest reduction in vascular volume compared to controls and either monotherapy (p<0.0001). Combination treatment resulted in durable anti-vascular activity with a significant (p<0.0001) reduction in blood volume (0.015±0.06) at the two week time point (Fig. 5B) compared to controls (0.75±0.05), ziv-aflibercept alone (0.14±0.06) and REGN1035 alone (0.20±0.04). No difference in perfusion (ΔR1) of kidneys was observed with single agent or combination treatments at both time points (Fig. S2). The panel of images shown in Figure 5C represent contrast enhancement maps of three contiguous slices of a tumor in each group at the end of two week treatment period. While single agent treatments resulted in reduction in perfusion compared to control tumors, combination treatment resulted in marked reduction in tumor growth and perfusion as evidenced by decreased contrast agent uptake in the tumor. Corresponding 3D MR angiography images of a representative tumor in all 4 groups is shown in Figure S3.

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