Inhibition of tumor growth in a VEGFR TKI-resistant model of renal cell carcinoma using dalantercept combined with sunitinib.

370 Background: Antagonists of VEGF/VEGFR pathway have demonstrated clinical utility in patients with metastatic renal cell carcinoma (RCC); however, the therapeutic responses tend to be short-lived. Thus, there is a need for new treatments to overcome the acquired resistance to the current standards of care. Methods: We have used a murine xenograft model of RCC to study the relationship of the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) superfamily pathways and the VEGF pathways. Additionally, we have studied the effects of BMP9/10 inhibition on RCC tumor growth and performed MRI based tumor blood flow analyses to study antiangiogenic activity of the treatments. To explore the role of BMP9/10/ALK1 signaling in resistance to VEGFR inhibition, we used dalantercept (human ALK1-Fc fusion protein) as a ligand trap for BMP9 and 10. Results: We have found evidence of upregulation of BMP10 in A498 RCC xenograft tumors that have developed resistance to sunitinib. In tumors that had devel...