DTIC ADA600725: A Novel Association and Therapeutic pdf

DTIC ADA600725: A Novel Association and Therapeutic

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We hypothesized that MUC1, a transmembrane glycoprotein that is overexpressed in 80% of pancreatic ductal adenocarcinoma induces a pro-angiogenic tumor microenvironment by increasing the level of NRP-1 and VEGF thereby enhancing angiogenesis and metastasis. We report that MUC1 (hi) PC cells and tumors in vitro and in vivo not only express higher levels of NRP1 but also express higher levels of VEGFR2, pVEGFR21175, pVEGFR2996, and VEGFR3 as well as secrete higher levels of VEGF than MUC1 (low) PC cells. This enables the MUC1 (hi)/NRPhi cells to generate long ectopic blood vessels and enhanced distant metastasis. In the proposal, we also hypothesized that blocking the interaction between VEGF165 and NRP-1 within the tumor microenvironment will lead to therapeutic benefit. Indeed, in vivo blocking NRP1 significantly reduces tumor burden in the MUC1hi tumors. In fact 4 out of 7 mice had a complete response, 2 had small tumors and 1 mouse did not respond and developed large tumor.

This treatment had no significant effect on the MUC1low tumors. This is not surprising since MUC1 (low) tumors have very low levels of NRP1 and VEGFR2. It should be noted that these MUC1 (low) tumors do however grow but may eventually form stable disease. Thus, we conclude that NRP1 may be a promising target for MUC1 (hi) PC and in the future conjugating to the MUC1 antibody for targeted delivery may enhance its potency

• Creator/s: Defense Technical Information Center
• Date: 10/1/2013
• Year: 2013
• Book Topics/Themes: DTIC Archive, , NORTH CAROLINA UNIV AT CHARLOTTE, *PANCREATIC DISEASES, ANGIOGENESIS, ANTIBODIES, BLOCKING, BLOOD VESSELS, METASTASIS, THERAPY

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