Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma
文献类型：期刊论文
| 作者 | Zhang, Xuesai1; Li, Qingrou1; Zhao, Hui1; Ma, Lanping2 ; Meng, Tao2; Qian, Jianchang1; Jin, Rui1; Shen, Jingkang2; Yu, Ker1
|
| 刊名 | ONCOTARGET
 |
| 出版日期 | 2017-08-29 |
| 卷号 | 8期号:35页码:59086-59102 |
| 关键词 | tissue factor triple negative breast cancer pancreatic adenocarcinoma metastasis antibody-drug conjugate |
| ISSN号 | 1949-2553 |
| DOI | 10.18632/oncotarget.19175 |
| 文献子类 | Article |
| 英文摘要 | The pathological presence of tissue factor (TF) in cancer cells promotes tumor-initiated thrombosis and cancer metastasis. We found that TF is aberrantly present in large percentage of aggressive triple negative breast cancer (TNBC) and pancreatic adenocarcinoma (PaC), two most lethal forms of malignancy that urgently need effective treatment. TF expression in TNBC clustered with higher levels of vimentin, basal-type keratins KRT5/14 and caveolin-1 but lower levels of luminaltype biomarkers. We developed a novel and specific anti-TF therapeutic antibody SC1, which displayed an exceedingly high potency against TF extracellular domain (EC50: 0.019 nM), TF-positive TNBC-or PaC cells (EC50: 2.5 nM), intracellular protease activated receptor 2 (PAR2) signaling (IC50: 2-3 nM) and tumor-initiated coagulation (IC50: < 10 nM). Depletion of TF or SC1-treatment in TNBC or PaC cells inhibited TF-induced cell migration, lung metastasis and tumor growth in vivo, accompanied by diminished levels of tumor angiogenesis and stromal fibrosis. We further propose TF as a promising target for antibody-drug conjugate (ADC) development based on its rapid and efficient internalization of SC1-drug conjugate. Both SC1-DM1 and SC1-MMAE elicited exquisite cytotoxicity in TF-positive TNBC and PaC cells (IC50: 0.02-0.1 nM) but not in TF-negative cells (> 100 nM) achieving > 5000 fold target selectivity. Following a weekly intravenous administration, SC1-MMAE and its humanized hSC1-MMAE inhibited TNBC-and PaC tumor growth achieving MED of 0.3-1 mg/kg and were both well tolerated. Thus, the prevalent TF expression in TNBC and PaC renders these challenging tumors highly susceptible to TF-targeted treatment and may offer new opportunity in cancer patients. |
| WOS关键词 | EPITHELIAL-MESENCHYMAL TRANSITION ; FACTOR CYTOPLASMIC DOMAIN ; GROWTH-FACTOR RECEPTOR ; TUMOR-GROWTH ; DUCTAL ADENOCARCINOMA ; COAGULATION CASCADE ; VENOUS THROMBOSIS ; COLORECTAL-CANCER ; DRUG CONJUGATE ; SOLID TUMORS |
| 资助项目 | Fudan University[EZF301002] ; National Natural Science Foundation of China[81273367] ; National Basic Research 973 Program of China[2013CB932500] |
| WOS研究方向 | Oncology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000408941900095 |
| 出版者 | IMPACT JOURNALS LLC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272518]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Yu, Ker |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Xuesai,Li, Qingrou,Zhao, Hui,et al. Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma[J]. ONCOTARGET,2017,8(35):59086-59102. |
| APA | Zhang, Xuesai.,Li, Qingrou.,Zhao, Hui.,Ma, Lanping.,Meng, Tao.,...&Yu, Ker.(2017).Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma.ONCOTARGET,8(35),59086-59102. |
| MLA | Zhang, Xuesai,et al."Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma".ONCOTARGET 8.35(2017):59086-59102. |
入库方式： OAI收割
来源：上海药物研究所
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