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.
Keywords:
ALK-1; VEGF; anti-angiogenic therapy; dalantercept; renal cell carcinoma.
MeSH terms
-
Activin Receptors, Type II / administration & dosage
-
Activin Receptors, Type II / antagonists & inhibitors*
-
Activin Receptors, Type II / genetics
-
Activin Receptors, Type II / metabolism
-
Animals
-
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
-
Axitinib
-
Carcinoma, Renal Cell / blood supply
-
Carcinoma, Renal Cell / drug therapy*
-
Carcinoma, Renal Cell / genetics
-
Cell Line, Tumor
-
Female
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Imidazoles / administration & dosage
-
Immunoglobulin Fc Fragments / administration & dosage
-
Indazoles / administration & dosage
-
Indoles / administration & dosage
-
Kidney Neoplasms / blood supply
-
Kidney Neoplasms / drug therapy*
-
Kidney Neoplasms / genetics
-
Mice, Nude
-
Neovascularization, Pathologic / genetics
-
Neovascularization, Pathologic / metabolism
-
Neovascularization, Pathologic / prevention & control*
-
Protein Kinase Inhibitors / administration & dosage
-
Pyrroles / administration & dosage
-
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
-
Receptors, Vascular Endothelial Growth Factor / genetics
-
Receptors, Vascular Endothelial Growth Factor / metabolism
-
Recombinant Fusion Proteins / administration & dosage
-
Sunitinib
-
Tumor Burden / drug effects
-
Tumor Burden / genetics
-
Xenograft Model Antitumor Assays
Substances
-
Imidazoles
-
Immunoglobulin Fc Fragments
-
Indazoles
-
Indoles
-
Protein Kinase Inhibitors
-
Pyrroles
-
Recombinant Fusion Proteins
-
Axitinib
-
Receptors, Vascular Endothelial Growth Factor
-
ACVRL1 protein, human
-
Activin Receptors, Type II
-
ALK1-Fc fusion protein, human
-
Sunitinib