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Updated: Jun 5, 2026
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma
Inga J Duignan1, Erik Corcoran, Anthony Pennello
1ImClone Systems, New York, NY 10016, USA.
Abstract:
The benefits of inhibiting vascular endothelial growth factor (VEGF) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells. Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells. However, recent data suggest that VEGF receptor (VEGFR)-specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels. Here, in fact, we demonstrate that DC101 (40 mg/kg, thrice a week), an antibody specific to murine VEGFR2, significantly reduces all three of these stromal components in subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma (RCC) established in nu/nu athymic mice. Sunitinib (40 mg/kg, once daily), a receptor tyrosine kinase inhibitor of VEGFR2 and other growth factor receptors, also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels. In combination, sunitinib did not significantly add to the effects of DC101 on tumor blood vessels, lymphatic vessels, or pericytes. Nevertheless, sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model, perhaps related to its broader specificity. Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma.
Insights
Targeting vascular endothelial growth factor receptor 2 (VEGFR2) with DC101 significantly impacts tumor stroma in renal cell carcinoma models. Combination therapy with sunitinib enhanced tumor burden reduction, suggesting broader therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Vascular Endothelial Growth Factor (VEGF) signaling inhibition primarily targets tumor endothelial cells.
- Targeting non-endothelial stromal cells is a strategy to enhance anti-cancer effects.
- VEGF receptor (VEGFR)-specific inhibitors may also affect lymphatic vessels and pericytes.
Purpose of the Study:
- To investigate the effects of VEGFR2 inhibition on tumor stroma in renal cell carcinoma (RCC) models.
- To compare the efficacy of a VEGFR2-specific antibody (DC101) and a multi-kinase inhibitor (sunitinib) on tumor stromal components.
- To evaluate the combination therapy of DC101 and sunitinib in RCC models.
Main Methods:
- Utilized subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma in nu/nu athymic mice.
- Administered DC101 (VEGFR2 antibody) and sunitinib (receptor tyrosine kinase inhibitor) at specified dosages and frequencies.
- Assessed the impact of treatments on tumor blood vessels, lymphatic vessels, and pericytes, as well as tumor burden.
Main Results:
- DC101 significantly reduced blood vessels, lymphatic vessels, and pericytes in both RCC models.
- Sunitinib showed significant loss of tumor blood vessels but had weaker effects on pericytes and lymphatics compared to DC101.
- Combination therapy did not enhance DC101's effects on stromal components but increased the reduction in tumor burden in one model.
Conclusions:
- Targeting VEGFR2 alone has pleiotropic effects on tumor stroma in renal cell carcinoma.
- Combination therapy with sunitinib may offer additional benefits in reducing tumor burden despite similar effects on stromal components.
- These findings have implications for designing combination therapies targeting VEGFR2 in RCC.
