A Novel Association and Therapeutic Targeting of Neuropilin-1 and MUC1 in Pancreatic Cancer
Technical Report,30 Sep 2012,29 Sep 2015
University of North Carolina at Charlotte Charlotte United States
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We hypothesized that MUC1, a transmembrane glycoprotein that is overexpressed in 80 of pancreatic ductal adenocarcinoma PDA induces a pro-angiogenic tumor microenvironment by increasing the level of NRP1 and VEGF there by enhancing angiogenesis and metastasis. We report that MUC1hi PC cells and tumors in vitro and in vivo not only express higher levels of NRP1 but also express higher levels of VEGFR2 and its phosphorylation forms as well as secrete higher levels of VEGF than MUC1 low PC cells. This enables the MUC1hiNRP1hi cells to induce endothelial cell tube formation and generate long ectopic blood vessels and enhanced distant metastasis. In the proposal, we also hypothesized that blocking the interaction between VEGF165 and NRP1 within the tumor microenvironment will lead to therapeutic benefit. Indeed, in vivo blocking NRP1 significantly reduces tumor burden in the MUC1hi mouse and human tumors. For the in vivo MUC1-specific tumor targeting, we demonstrate that the antibody TAB004 binds MUC1ve tumors in vitro and in vivo by Immunohistochemistry of primary human PDA tissues and by live animal imaging. Thus, NRP1 is a promising target for MUC11hi PDA. We conjugated TAB 004 to the a specific NRP-inhibitor for in vivo targeted therapy and show higher efficacy ofthe conjugate as compared to TAB004 alone or NRP-inhibitor alone in reducing VEGF secretion.