Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma.

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.

• Authors: Xiaoen Wang, Nicolas Solban, Prateek Khanna, Marcella Callea, Jiaxi Song, David C Alsop, R Scott Pearsall, Michael B Atkins, James W Mier, Sabina Signoretti, Marat Alimzhanov, Ravi Kumar, Manoj K Bhasin, Rupal S Bhatt
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 27 Pg. 41857-41869 (Jul 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27248821 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Activin Receptors, Type II (administration & dosage, antagonists & inhibitors, genetics, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Axitinib
• Carcinoma, Renal Cell (blood supply, drug therapy, 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, drug therapy, genetics)
• Mice, Nude
• Neovascularization, Pathologic (genetics, metabolism, prevention & control)
• Protein Kinase Inhibitors (administration & dosage)
• Pyrroles (administration & dosage)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, genetics, metabolism)
• Recombinant Fusion Proteins (administration & dosage)
• Sunitinib
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays