Abstract
Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development of combination therapies that can extend the efficacy of VEGFR antagonists in mRCC remains a priority.We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib. Dalantercept is a novel antagonist of Activin receptor-like kinase 1 (ALK1)/Bone morphogenetic protein (BMP) 9 signaling. Dalantercept inhibited growth in the murine A498 xenograft model which correlated with hyperdilation of the tumor vasculature and an increase in tumor hypoxia. When combined with sunitinib, dalantercept induced tumor necrosis and prevented tumor regrowth and revascularization typically seen with sunitinib monotherapy in two RCC models. Combination therapy led to significant downregulation of angiogenic genes as well as downregulation of endothelial specific gene expression particularly of the Notch signaling pathway.We demonstrate that simultaneous targeting of molecules that control distinct phases of angiogenesis, such as ALK1 and VEGFR, is a valid strategy for treatment of mRCC. At the molecular level, combination therapy leads to downregulation of Notch signaling.
Highlights
An increased understanding of the molecular biology of RCC has led to the identification of angiogenesis as a key contributor to its pathogenesis
We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib
We demonstrate that simultaneous targeting of molecules that control distinct phases of angiogenesis, such as Activin receptor-like kinase 1 (ALK1) and VEGFR, is a valid strategy for treatment of metastatic renal cell carcinoma (mRCC)
Summary
An increased understanding of the molecular biology of RCC has led to the identification of angiogenesis as a key contributor to its pathogenesis. Multiple antagonists of the VEGF signaling pathway such as the multikinase inhibitors sunitinib, pazopanib, axitinib and sorafenib and the monoclonal antibody to VEGFA, bevacizumab, are approved for treatment of patients with advanced RCC [1,2,3,4]. We have shown by IHC and ASL MRI, that the development of sunitinib-resistant vessels is inhibited by supplemental activation of endogenous angiostatic pathways such as CXCL9 [5] Based on these findings, we hypothesize that optimal antiangiogenic regimens will include combinations of agents targeting different steps in tumor angiogenesis
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