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 developed resistance to sunitinib, addition of ALK1-Fc to sunitinib led to prolonged tumor stabilization compared to either agent alone. Imaging of tumors revealed that addition of ALK1-Fc to sunitinib prevented the resumption in blood flow that is generally seen with continued sunitinib. CONCLUSIONS These murine xenograft model data demonstrate that inhibition of ALK1 receptor pathway in combination with inhibition of VEGFR pathway may be a useful strategy for the treatment of RCC. A phase II randomized study of dalantercept in combination with axitinib in patients with metastatic RCC after progression on VEGFR/TKI therapy is ongoing.