Abstract 3272: A Met receptor docking site peptide fused to cell-penetrating sequences acts as a powerful inhibitor of angiogenesis and vascular tumour growth

Abstract

Abstract Introduction: Hepatocyte growth factor (HGF) is a potent mitogenic, motogenic and morphogenic factor with angiogenic properties; it directly or indirectly stimulates endothelial cells favouring tumour expansion and HGF receptor activation in cancer cells. Kaposi's sarcoma (KS), the most frequent neoplasia in patients with AIDS, which originates from endothelial origin and is highly vascularized, shows features compatible with the biological properties of HGF. We decided to develop angiogenesis inhibitors that target the HGF pathway, impairing tumour neo-vascularization and metastatic spreading. We investigated the anti-angiogenic properties of synthetic peptides mimicking the docking site of Met receptor on human endothelial cells (HUVEC) and KS. We also analyzed the role of diacylglycerol kinases (DGK) in KS cell responses. Material and methods: To evaluate the effect of Met-derived inhibitors on angiogenesis, we treated HUVEC with peptides containing Met docking site fused to the internalization sequences of Antennapedia homeodomain or of Tat transactivation domain which were used to deliver peptides into living cells. We evaluated the ability of peptides to interfere with HGF-induced proliferation, migration and morphogenesis of endothelial cells in vitro and angiogenesis and tumor growth in vivo. To investigate the role of DGK in the different biological responses elicited by HGF in the Kaposi’ sarcoma cells, we treated KS cells with the DGK pharmacological inhibitor R59949. Results: We observed that in endothelial cells internalized peptides inhibited ligand-dependent cell proliferation, motility, invasiveness and morphogenesis in vitro, which correlated with interference of HGF-dependent downstream signalling. In vivo, the peptides inhibited HGF-induced angiogenesis and Kaposi's sarcoma tumour growth. DGK plays an essential role in KS cell proliferation. Conclusion: the data obtained on endothelial cells show that the carboxyl-terminal sequence of Met fused to the internalization sequences of Antennapedia homeodomain or of Tat transactivation domain impairs angiogenesis triggered by HGF, suggesting the use of anti-docking site compounds as therapeutic agents to interfere with the angiogenesis process. The demonstration that DGK is essential for KS growth suggests that these enzymes are promising target for a pharmacological intervention on KS cells. The development of angiogenesis inhibitors and the identification of new intracellular transducers effective in the high vascularised KS cells, open the possibility of a combination therapy that concomitantly interferes with tumour neo-vascularization and the malignant properties of KS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3272. doi:10.1158/1538-7445.AM2011-3272