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

• DOI: 10.18632/oncotarget.9621
• Publication Date: 2016-05-26T15:34:42Z
• 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
• Keywords: 0301 basic medicine; renal cell carcinoma; Indazoles; Indoles; Axitinib; Activin Receptors, Type II; Recombinant Fusion Proteins; 610; Mice, Nude; anti-angiogenic therapy; 03 medical and health sciences; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Pyrroles; Carcinoma, Renal Cell; Protein Kinase Inhibitors; ALK-1; Neovascularization, Pathologic; Imidazoles; VEGF; Kidney Neoplasms; Immunoglobulin Fc Fragments; 3. Good health; Gene Expression Regulation, Neoplastic; Receptors, Vascular Endothelial Growth Factor; Female; dalantercept; Research Paper

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.