Abstract LB-313: ALK1-Fc inhibits tumor growth in a VEGF pathway resistance model of renal cell carcinoma
Authors: Xiaoen Wang, Nicolas Solban, Manoj K. Bhasin, Brittany Bahamon, Liang Zhang, Sabina Signoretti, David C. Alsop, Michael B. Atkins, R. Scott Pearsall, James W. Mier, Ravindra Kumar, Rupal S. Bhatt
Journal: Cancer Research (2012)

Abstract 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 naïve 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&amp;lt;0.01). Single agent ALK1-Fc did not show activity in the 786-O model; however combination ALK1-Fc + sunitinib slowed tumor growth to a greater extent than either agent alone or vehicle tumors in both the A498 and the 786-O tumor models. A498 tumors treated with sunitinib took 13.8+/−2.5 days (n=4) to increase by 2 mm vs the ALK1-Fc + sunitinib combination (35 +/− 12.6 days (n=4) (p=0.01)). 786-O derived tumors, treated with sunitinib took 24.7+/−8.3 days (n=3), while tumors treated with combination of ALK1-Fc + sunitinib took 43.7+/−4.2 days (n=3, p&amp;lt;0.03) to grow by 2 mm. Perfusion imaging of these tumors revealed that sunitinib + ALK-Fc lowers perfusion more than sunitinib treated tumors. Our data indicate that ALK1-Fc treatment can act as a single agent to delay tumor growth in at least 1 RCC xenograft model. In addition, combination therapy with ALK1-Fc and sunitinib further delays tumor growth vs either agent administered alone. The effect of the combination therapy on vessel formation and tumor perfusion are currently being investigated. The differential response to ALK1-Fc treatment in the A498 compared to the 786-O cell lines provides an opportunity to explore the molecular and pathological differences between the two models, which may allow for better insight into mechanisms of action and future pt selection. The data demonstrate that blocking ligand signaling through the endogenous ALK1 receptor, either alone or in combination with other antiangiogenic therapies, is a valid strategy for treatment of RCC. 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