Abstract 1692: Dalantercept, an ALK1 inhibitor of angiogenesis, in combination with cisplatin inhibits tumor growth in a xenograft model of squamous cell carcinoma of the head and neck

Abstract

Abstract Activin receptor-like kinase 1 (ALK1) is a key regulator of angiogenesis and vascular morphogenesis. ALK1 and its co-receptor endoglin are selectively expressed on the surface of activated endothelial cells during angiogenesis. Bone morphogenetic proteins (BMP) 9 and 10 are ligands that bind to ALK1 and induce activation of the heteromeric receptor complex, phosphorylation of SMAD1/5/8, and upregulation of specific genes involved in the maturation stage of angiogenesis, such as Id-1 and TMEM100. In particular, BMP9 expression is upregulated in a majority of squamous cell carcinomas of the head and neck (SCCHN). Dalantercept is an ALK1 extracellular domain-Fc fusion protein that binds BMP9 and BMP10 with high affinity and antagonizes ALK1 signaling in vivo resulting in defective vascular maturation and inhibition of tumor growth in preclinical models. In a completed Phase 1 trial in patients with advanced, refractory solid tumors dalantercept demonstrated signs of clinical activity in a variety of patients, including two of three patients with SCCHN who achieved either an objective response or prolonged stable disease. A Phase 2 trial of dalantercept as monotherapy in recurrent/metastatic SCCHN patients who have had prior platinum-based chemotherapy is currently ongoing. Based upon the single agent activity of both dalantercept and cisplatin in SCCHN, we tested the feasibility of the combination of cisplatin plus dalantercept in a mouse model of SCCHN. Combination treatment of dalantercept plus cisplatin showed significant tumor growth inhibition (TGI) in the RPMI2650 xenograft model (59% TGI on day 30) which was significantly better than either cisplatin (35% TGI, p= 0.0077) or dalantercept (32% TGI, p=0.0002) alone. No additional toxicity was observed in the combination treatment group compared to cisplatin monotherapy group. These data suggest that combination of dalantercept plus cisplatin may result in enhanced clinical activity and supports prospective evaluation in patients with SCCHN. Citation Format: Marat Alimzhanov, Michael Lee, Nicolas Solban, Scott Pearsall, Susan Pandya, Matthew L. Sherman, Ravindra Kumar. Dalantercept, an ALK1 inhibitor of angiogenesis, in combination with cisplatin inhibits tumor growth in a xenograft model of squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2014-1692