Abstract B70: Targeting the Tie2/angiopoietin signaling pathway in glioblastoma

Abstract

Abstract Angiogenesis inhibitors have evolved in the past decade as one of the most promising biology based therapeutic strategies. Promising pre-clinical studies (published in 1993 and 1994) provided proof of principle that blocking of VEGF dramatically inhibits tumor growth. These observations led to the successful development of inhibitors for VEGF and VEGF receptors by various pharmaceutical companies. Bevacizumab, a monoclonal antibody neutralizing VEGF, was the first-in class drug to achieve FDA approval for the treatment of colorectal carcinoma in 2004 and later on in other cancer types, including glioblastoma. Anti-VEGF therapy led to an increase in progression free survival in recurrent and primary GBM, but its role in first-line treatment is less clear. Importantly, several preclinical studies suggested that resistance to anti-angiogenic therapy might evolve in the course of the treatment due to an infiltration of specially polarized myeloid cells. In order to define new therapeutic options for anti-angiogenic therapy we investigated the Tie2/Angiopoietin (Angpt) signaling pathway in human and murine glioblastomas. In more than 200 human brain tumor specimens investigated, Angpt2 protein expression was found to be up-regulated in tumor endothelial cells whereas it was absent in the normal brain. Further, Angpt2 expression levels correlated with WHO grade as well as the number of infiltrating monocytes/macrophages. Notably, transgenic mice with endothelial cell-specific expression of Angpt2 showed a significant higher number of infiltrating myeloid cells, thus corroborating our findings in human GBM. These findings suggest, that Angpt signaling links inflammation and angiogenesis in GBM and may thus provides a therapeutic target. In a GL261 orthotopic syngeneic glioma model, interference with Angpt signaling with pharmacologic agents and peptide-based blockers of Angpt2, lead to a significant increase in survival, increased pericyte coverage and altered myeloid cell/T-cell composition. Combining anti-Angpt with anti-VEGF based therapies showed synergistic effects. These findings argue for targeting the Tie2/Angpt signalling pathways in human GBM, either alone or in combination with anti-VEGF therapies. Citation Format: Karl H. Plate, Alexander Scholz, Patrick Harter, Michel Mittelbronn, Paul van Slyke, Dan Dumont, Yvonne Reiss. Targeting the Tie2/angiopoietin signaling pathway in glioblastoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B70. doi:10.1158/1538-7445.CHTME14-B70