Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma
| Autor: | Marat Alimzhanov, Sabina Signoretti, David C. Alsop, Manoj Bhasin, Jiaxi Song, James W. Mier, Rupal S. Bhatt, Xiaoen Wang, Michael B. Atkins, Nicolas Solban, R. Scott Pearsall, Marcella Callea, Ravi Kumar, Prateek Khanna |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
renal cell carcinoma Indazoles Indoles Combination therapy Axitinib Angiogenesis Activin Receptors Type II Recombinant Fusion Proteins Notch signaling pathway Mice Nude urologic and male genital diseases anti-angiogenic therapy 03 medical and health sciences Downregulation and upregulation Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Dalantercept medicine Sunitinib Animals Humans Pyrroles Carcinoma Renal Cell Protein Kinase Inhibitors ALK-1 Tumor hypoxia Neovascularization Pathologic business.industry Imidazoles Kinase insert domain receptor Xenograft Model Antitumor Assays VEGF Kidney Neoplasms 3. Good health Immunoglobulin Fc Fragments Tumor Burden Gene Expression Regulation Neoplastic 030104 developmental biology Receptors Vascular Endothelial Growth Factor Oncology Immunology Cancer research Female business medicine.drug Research Paper dalantercept |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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