Inhibition of EP1 in conjunction with Sorafenib for liver cancer chemoprevention

抑制 EP1 与索拉非尼联合用于肝癌化学预防

• 批准号: 7748213
• 负责人: Chang Han
• 金额: $ 1.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748213
• 关键词: Adverse effects; Animal Model; BAY 54-9085; Biliary; Cancer Cell Growth; Carcinogenesis Inhibition; Carcinogens; Carcinoma; Cardiovascular system; Chemoprevention; Cholangiocarcinoma; Chronic; Chronic Hepatitis C; Coxibs; Development; Diethylnitrosamine; Dinoprostone; Dose; Dysplasia; Epithelial; Exhibits; FDA approved; Future; Grant; Hand; Hepatic; Hepatobiliary; Hepatocarcinogenesis; Human; Incidence; Inflammation; Inflammatory; Intrahepatic Cholangiocarcinoma; Laboratories; Liver diseases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Molecular Target; Natural regeneration; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipase; Play; Primary carcinoma of the liver cells; Process; Production; Prostaglandin Receptor; Prostaglandins; Prostaglandins I; Publishing; Reaction; Role; Signal Transduction; Skin; Therapeutic; United States; base; cancer chemoprevention; carcinogenesis; cyclooxygenase 2; foot; high risk; inhibitor/antagonist; intrahepatic; novel; primary sclerosing cholangitis; prostanoid receptor EP1; public health relevance; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Primary liver cancers are highly malignant tumors in human and their incidences are rising in the United States. The overall survival of patients with liver cancer is grim and currently no efficient chemoprevention is available. On the basis of our published and ongoing studies, we hypothesize that the EP1 receptor plays a key role in prostaglandin-induced hepatic carcinogenesis and that inhibition of EP1 in combination with the multikinase inhibitor, sorafenib, may represent a novel and safe approach for effective chemoprevention. This hypothesis will be examined in the two specific aims using complementary animal models of hepatic carcinogenesis. Aim 1 will evaluate the combination effect of EP1 inhibition and sorafenib on the development of hepatocellular cancer induced by the hepatic carcinogen, diethylnitrosamine. Aim 2 will examine the combination effect of EP1 inhibition and sorafenib on the development of intrahepatic cholangiocellular carcinoma induced by Pten/Smad4 disruption. The proposed studies are expected to provide important implications for future chemoprevention of human liver cancer.

描述（由申请人提供）： 原发性肝癌是人类高度恶性的肿瘤，在美国的发病率正在上升。肝癌患者的总体生存率是严峻的，目前没有有效的化学预防。基于我们已发表和正在进行的研究，我们假设EP 1受体在依那普利诱导的肝癌发生中起着关键作用，并且EP 1与多激酶抑制剂索拉非尼联合抑制可能代表了一种有效化学预防的新的安全方法。这一假设将在两个特定的目标，使用互补的动物模型的肝癌。目的1将评估EP 1抑制和索拉非尼对肝癌原二乙基亚硝胺诱导的肝细胞癌发展的联合作用。目的2将检查EP 1抑制和索拉非尼对Pten/Smad 4破坏诱导的肝内胆管细胞癌的发展的联合作用。这些研究为今后肝癌的化学预防提供了重要的参考。