Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma
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Xiaoen Wang2, Nicolas Solban3, Prateek Khanna1, Marcella Callea4, Jiaxi Song4, David C. Alsop2, R. Scott Pearsall3, Michael B. Atkins5, James W. Mier1, Sabina Signoretti4, Marat Alimzhanov3, Ravi Kumar3, Manoj K. Bhasin6, Rupal S. Bhatt1
1Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
3Acceleron Pharma, Inc., Cambridge, MA, USA
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
5Departments of Oncology and Medicine, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
6Division of Interdisciplinary Medicine & Biotechnology, and Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
Rupal S. Bhatt, email: email@example.com
Manoj K. Bhasin, email: firstname.lastname@example.org
Keywords: renal cell carcinoma, anti-angiogenic therapy, ALK-1, VEGF, dalantercept
Received: February 03, 2016 Accepted: May 05, 2016 Published: May 26, 2016
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.
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