Alk1-Fc Inhibits Tumor Growth In A Vegf Pathway Resistance Model Of Renal Cell Carcinoma

Treatment of metastatic RCC with agents that block signaling through VEGFR2 induces disease stabilization or regression in a substantial fraction of patients (pts); however, these responses tend to be short-lived. Mice bearing 786-O and A498 human RCC xenografts treated with sunitinib or sorafenib also exhibit a period of tumor stabilization followed by the resumption of growth and restoration of angiogenesis despite continued drug administration. Thus, alternate angiogenic pathways are of interest in the treatment of RCC. Activin receptor-like kinase 1 (ALK1) is one of 7 type I TGFβ receptors which is predominantly expressed on activated vascular endothelial cells. ALK1-Fc is a soluble receptor fusion protein containing the extracellular domain of ALK1 linked to a human Ig Fc region. ALK1-Fc binds to and neutralizes the activity of bone morphogenetic protein 9 and 10 (BMP9, 10) and has demonstrated antiangiogenic activity in vivo. Currently, ALK1-Fc (ACE-041) is undergoing clinical development. We have found evidence of TGFβ pathway upregulation in tumors that have developed resistance to sunitinib. Thus, to explore the role of ALK signaling in the treatment of RCC we administered ALK1-Fc to mice bearing RCC xenografts. In the treatment naive A498 model, administration of ALK1-Fc alone delayed tumor growth relative to vehicle: days to grow by 2 mm vehicle- 5.8 +/−0.96 days (n=5) vs ALK1-Fc- 10.8 +/− 1.7 days (n=4, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-313. doi:1538-7445.AM2012-LB-313