Abstract IA16: Combinatorial targeting of angiogenic growth factor pathways

Abstract

Abstract Solid tumors require blood vessels for growth and dissemination, and use lymphatic vessels as additional conduits for metastatic spread. Most of the current anti-angiogenic therapies are targeted against the vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. However, in many cases resistance to the therapy occurs, and thus far the clinical therapeutic benefit has been limited to only modest improvements in overall survival. Therefore, novel treatment modalities are required. The major angiogenic pathways include a family of five VEGFs and their three receptors. I will discuss the other members of the VEGF-VEGFR family, as well as two of the three angiopoietin growth factors and their receptors Tie1 and Tie2 as targets for the inhibition of tumor angiogenesis and metastasis. Biochemical, cell biological and genetic experiments have revealed the crosstalk between the pathways, their activation mechanisms and their essential functions in tissues. These studies have shown that even the Tie1 receptor, which does directly not bind angiopoietins, but is part of the angiopoietin-receptor complex, is crucial for tumor angiogenesis and growth. Some of the angiopoietin signals also regulate vessel stability and the delivery of therapeutics to the tumor. Furthermore, recent results have indicated that integrin-mediated angiopoietin-2 signals can induce vessel destabilization. Combinatorial blocking of multiple angiogenic growth factor pathways shows promise in improving the efficacy of anti-angiogenic therapy without significantly increasing its side-effects. Citation Format: Kari K. Alitalo. Combinatorial targeting of angiogenic growth factor pathways. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA16.