Abstract B217: Annexin A2 is a novel molecular target for TM601, a peptide with specific tumor targeting and antiangiogenic properties

Abstract

Abstract In this study we sought to identify the cell surface target for TM601, a peptide with tumor-targeting and anti-angiogenic effects. The 131I-radiolabeled form of TM601 is currently in clinical trials for having been shown to specifically bind several human tumor types including malignant glioblastoma, colorectal, pancreatic, prostate and non-small cell lung carcinomas. We used a biochemical approach of surface cross-linking followed by affinity-binding assays in conjunction with mass spectrometry and siRNA knock-down to identify and validate the target for TM601 on tumor and vascular endothelial cell. We identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and HUVEC vascular endothelial cells. We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line, Panc-1 is dependent on the expression of annexin A2. Annexin A2 is over-expressed in several human cancers and has functions in angiogenesis by binding to tissue plasminogen activator (tPA) and regulating plasminogen activation on vascular endothelial cells. In HUVEC cells, TM601 inhibits both VEGF and bFGF induced tPA activation which is in turn required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits PDGF-CC induced trans-well migration of both HUVEC vascular endothelial and U373-MG glioma cells. In conclusion, we have identified annexin A2 as a novel cell surface target for TM601 that might mediate both the tumor-targeting and anti-angiogenic effects of the peptide. Importantly, our results also support a role annexin A2 as a molecular target in cancer therapeutics. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B217.