Abstract 5080: Inhibiting the ALK1/BMP9 signaling pathway with dalantercept as an antiangiogenic therapy.

Abstract

Abstract Activin receptor-like kinase 1 (ALK1) is an endothelial cell-specific receptor for bone morphogenetic proteins (BMP) 9 and 10, and is a key regulator of angiogenesis and vascular morphogenesis. Preclinical data suggest that the BMP9/ALK1 pathway is operating in the resolution and maturation stage of angiogenesis, which is distinct from the VEGF/VEGFR pathway which drives the initiation stage of angiogenesis. Dalantercept is an ALK1 extracellular domain-Fc fusion protein that inhibits the BMP9/ALK1 pathway. Thus, dalantercept may prove useful either as a monotherapy to inhibit tumor angiogenesis or in combination with VEGFR inhibitors to target different phases of vascular network formation and potentially to overcome acquired resistance to anti-VEGF therapy. To test this hypothesis, the A498 renal cell carcinoma xenograft model was used to test dalantercept efficacy either alone or in combination with sunitinib. In this model, tumor progression was defined as a 2 mm increase in tumor length. In the placebo group, mean (± SD) tumor progression was 5.8 ±0.6 days. Treatment with dalantercept delayed tumor progression to 10.8 ± 1.7 days (p<0.01 vs placebo) and sunitinib delayed tumor progression to 13.8 ± 2.5 days (p<0.01 vs placebo). The combination treatment of dalantercept plus sunitinib had a greater beneficial effect with a delay in tumor progression to 35 ± 12.6 days (p=0.01 vs sunitinib). We used immunohistochemistry (IHC) analysis to evaluate effects of dalantercept on tumor vasculature and to look for potential biomarkers of response to treatment in A498 tumors. Id1 is a transcription factor expressed in endothelial cells and is known to be regulated via the BMP9/ALK1/SMAD pathway. We observed a decrease in Id1 protein expression in endothelial cells of A498 xenografts treated with dalantercept, consistent with our previous experiments. Because BMP9 is one of the main target ligands of dalantercept, IHC analysis of archived human tumor samples was performed to determine BMP9 expression levels in various tumor types. In squamous cell carcinoma of the head and neck it was shown that out of 28 tumor samples 79% had high or medium levels of BMP9 staining, with little to no staining in normal tissues. Data from BMP9 expression in renal cell carcinoma and hepatocellular carcinoma will also be presented. In a Phase 1 study in patients with advanced, refractory solid tumors, dalantercept was generally well tolerated and exhibited signs of clinical activity including patients with objective response and prolonged stable disease. Dalantercept is currently being tested in several Phase 2 oncology studies, including a study of dalantercept in combination with the anti-VEGFR TKI axitinib in second-line advanced renal cell carcinoma. Citation Format: Marat Alimzhanov, Nicolas Solban, Michael Lee, Phaethon Philbrook, Xiaoen Wang, Lin Wei, Jiaxi Song, Sabina Signoretti, R. Scott Pearsall, Matthew L. Sherman, Ravindra Kumar, Rupal S. Bhatt. Inhibiting the ALK1/BMP9 signaling pathway with dalantercept as an antiangiogenic therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5080. doi:10.1158/1538-7445.AM2013-5080