Abstract 5079: Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-Endoglin antibodies.

Citations Over Time

Abstract

Abstract Endoglin (ENG), a co-receptor for several TGFβ-family cytokines, is expressed in activated endothelial cells alongside ALK1, the ACVRL1 gene product. ENG and ACVRL1 are both required for angiogenesis and mutations in either gene are associated with Hereditary Hemorrhagic Telangectasia, a rare genetic vascular disorder. ENG and ALK1 function in the same genetic pathway but the relative contribution of TGFβ and BMP9 to SMAD1/5/8 activation and the requirement of ENG as a co-mediator of SMAD phosphorylation in endothelial cells remain debated. Here, we show that BMP9 and TGFβ1 induce distinct SMAD phosphorylation responses in primary human endothelial cells and that, unlike BMP9, TGFβ1 only induces SMAD1/5/8 phosphorylation in a subset of immortalized mouse endothelial cell lines, but not in primary human endothelial cells. We also demonstrate, using siRNA depletion of ENG and novel neutralizing anti-ENG antibodies, that ENG is required for BMP9/pSMAD1 signaling in all human and mouse endothelial cells tested. Finally, anti-ENG antibodies that interfere with BMP9/pSMAD1 signaling, but not with TGFβ1/pSMAD3 signaling, including the TRC105 clinical candidate, also decrease in vitro HUVEC endothelial tube formation and inhibit BMP9 binding to recombinant ENG in vitro. Our data demonstrate that BMP9 signaling inhibition is a key and previously unreported mechanism of action of TRC105, an anti-angiogenic anti-ENG antibody currently evaluated in clinical trials. Citation Format: Olivier P. Nolan-Stevaux, Wendy Zhong, Dineli Wickramasinghe, Astrid Ruefli-Brasse. Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-Endoglin antibodies. [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 5079. doi:10.1158/1538-7445.AM2013-5079

Related Papers

• → Endoglin (CD105): A Marker of Tumor Vasculature and Potential Target for Therapy(2008)351 cited
• → CD105 (Endoglin) as negative prognostic factor in AML(2019)27 cited
• Evaluation of Endoglin as an Angiogenesis Marker in Glioblastoma.(2015)
• Expression of Smad 2 and Smad 4 proteins in brain tissue following cerebral ischemia/reperfusion in gerbils(2008)
• Research progress in CD105 and its relation with tumors(2007)