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

// Xiaoen Wang 2 , Nicolas Solban 3 , Prateek Khanna 1 , Marcella Callea 4 , Jiaxi Song 4 , David C. Alsop 2 , R. Scott Pearsall 3 , Michael B. Atkins 5 , James W. Mier 1 , Sabina Signoretti 4 , Marat Alimzhanov 3 , Ravi Kumar 3 , Manoj K. Bhasin 6 , Rupal S. Bhatt 1 1 Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 2 Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 3 Acceleron Pharma, Inc., Cambridge, MA, USA 4 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 5 Departments of Oncology and Medicine, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA 6 Division of Interdisciplinary Medicine & Biotechnology, and Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA Correspondence to: Rupal S. Bhatt, email: rbhatt@bidmc.harvard.edu Manoj K. Bhasin, email: mbhasin@bidmc.harvard.edu Keywords: renal cell carcinoma, anti-angiogenic therapy, ALK-1, VEGF, dalantercept Received: February 03, 2016     Accepted: May 05, 2016     Published: May 26, 2016 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.