演題抄録

一般演題 (示説)

開催概要
開催回
第53回・2015年・京都
 

肝胆膵領域癌に対する治療標的としてのASPHの解析

演題番号 : P131-4

[筆頭演者]
藍原 有弘:1,2 
[共同演者]
Huang Chiung-kuei:2、Olsen Mark:3、Chung Waihong:2、Tang Qi:4、Dong Xiaoqun:4、田中 真二:5、田邉 稔:1、Wands Jack:2

1:東京医科歯科大学大学院医歯学総合研究科肝胆膵外科、2:Liver Research Center, Brown University、3:Department of Pharmaceutical Sciences, Midwestern University、4:Department of Biomedical and Pharmaceutical Science, The University of Rhode Island、5:東京医科歯科大学大学院医歯学総合研究科分子腫瘍医学

 

Background: Hepatobiliary cancer and pancreatic cancer have a poor prognosis due to aggressive progression and metastatic spread. Aspartate beta-hydroxylase (ASPH), a cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands, is highly overexpressed in hepatocellular carcinoma and pancreatic cancer.
Methods: Levels of ASPH expression were evaluated by immunohistochemistry (IHS) in human clinical samples of Hepatocellular carcinoma (HCC) and pancreatic cancer (PC). Small molecule inhibitors (SMIs) were designed based on the crystal structure of the ASPH catalytic site followed by computer assisted drug design. In order to test candidate compounds for inhibition of β-hydroxylase activity, a CO2 capture assay was performed. Effects of SMIs on cancer cells were evaluated by migration/invasion, colony formation and anchorage independent colony formation assays. In vivo efficacy was investigated using murine xenograft models. The biologic effects of SMI were explored through analysis of the Notch signaling cascade by Western blotting and IHS.
Results: ASPH was expressed in 22 of 27 human HCC tumors (81.3%) and 101of 104 human PC tumors (97.14%). A SMI of ASPH was developed and inhibited enzymatic activity of ASPH by 78%, which reduced cell viability of hepatocellular carcinoma and pancreatic cancer cell lines, and suppressed cell motility and invasiveness in in vitro. Reduction of tumor growth was observed in the murine xenograft subcutaneous model of HCC and PC. The ASPH inhibitor also inhibited expression of downstream targets of the Notch signaling pathway (HES1 and HEY1) both in vitro and in vivo.
Conclusions: ASPH is an attractive molecular target for hepatobiliary pancreatic malignancy

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臓器別:肝臓

手法別:トランスレーショナルリサーチ

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