Inhibition of pancreatic carcinogenesis via targeting c-Raf and sEH

通过靶向 c-Raf 和 sEH 抑制胰腺癌发生

基本信息

批准号：
9056497
负责人：
Guang-Yu Yang
金额：
$ 32.03万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056497
关键词：
Acids Animals Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids BAY 54-9085 Benzoic Acids Blood Caerulein Cancer cell line Cells Cytochrome P450 Data Development Dose Drug Kinetics Early Diagnosis Ensure Enzymes Epoxide hydrolase Event Exhibits Gene Expression Gene Mutation Growth Health Human Hydrolase In Vitro Inflammation Inflammatory Knock-out Lead MAP Kinase Gene MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Modeling Molecular Mus Mutation NF-kappa B Oral Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Carcinoma Pancreatic Intraepithelial Neoplasia Pancreatitis Phosphorylation Picolinic Acids Play Prevention Prevention strategy Risk Factors Role Sampling Signal Transduction TP53 gene Testing Time Toxic effect Vascular Cell Adhesion Molecule-1 Vascular Endothelial Growth Factors attenuation base carcinogenesis chronic pancreatitis cytokine design flexibility in vivo inhibitor/antagonist kinase inhibitor knockout gene mortality mouse model mutant novel overexpression pancreatic tumorigenesis small molecule success tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The significance of this project is to develop an efficient agent for the prevention of highly lethal pancreatic cancer through targeting both c-Raf and sEH. Early detection and prevention is of great importance to reduce the mortality of pancreatic cancer. Mutant Kras is the most common and earliest molecular event involved in human pancreatic carcinogenesis; and using mutant Kras-initiated tumorigenesis in mice, it has been demonstrated that c-Raf is required for Kras-initiated tumorigenesis and knockout c-Raf blocks Kras- initiated cancer development. Chronic pancreatitis is a well-recognized risk factor of pancreatic cancer. In mutant Kras-initiated pancreatic tumorigenesis in Pdx1-Cre/LSL-KrasG12D mice (called PanKras), caerulein- induced pancreatitis enhances malignant progression. In addition to pancreatitis, mutant Kras cooperates with mutant p53 (the second most common genetic alteration) leading to pancreatic cancer development in mice, mainly via synergistically regulating ERK-MAPK and NF-kB. Anti-inflammatory EETs are quickly inactivated by pro-inflammatory soluble epoxide hydrolase (sEH). Our preliminary data showed that 1) 96% (27/28) and 90% (27/30) of human pancreatic adenocarcinoma samples displayed a distinct over-expression of sEH and p-c-Raf, respectively, and 2) our novel dual c-Raf/sEH inhibitor t-CUPM exhibited strong inhibitory effect on pancreatitis and mPanIN formation in PanKras mice. Our hypothesis is that c-Raf and sEH play key roles in pancreatic carcinogenesis initiated by mutant Kras and enhanced by pancreatitis or mutant p53; and targeting these two enzymes together is a novel and relevant preventive strategy for pancreatic cancer. Three specific aims are proposed to test this hypothesis: 1) to determine the effects of c-Raf/sEH dual inhibitor t-CUPM, sEH inhibitor t- AUCB and Raf inhibitor Raf265/sorafenib on mutant Kras-initiated and pancreatitis-enhanced carcinogenesis in PanKras mice; 2) to determine whether blocking mutant Kras-activated c-Raf using inhibitors or gene knockout suppresses mutant Kras-p53 interaction and malignant progression in Pdx1-KrasG12D-p53R172 mice; and 3) to determine the role of sEH in pancreatitis and carcinogenesis using the approach of sEH gene knockout in PanKras mice. Successfulness of the proposed study will not only lead us to demonstrate the role of c-Raf and sEH in pancreatic carcinogenesis, but also to establish a significance of t-CUPM as a novel agent for inhibiting the pancreatic cancer development.

描述（由申请人提供）：该项目的重要性是通过针对C-RAF和SEH来开发一种有效的药物来预防高致命的胰腺癌。早期发现和预防对于降低胰腺癌的死亡率至关重要。突变的KRAS是人类胰腺癌作用涉及的最常见和最早的分子事件。并使用突变的KRAS引起的小鼠肿瘤发生，已经证明C-RAF是KRAS引起的肿瘤发生所必需的，而基因敲除C-RAF阻断了KRAS的癌症开发。慢性胰腺炎是胰腺癌公认的危险因素。在突变的KRAS引起的PDX1-CRE/LSL-KRASG12D小鼠（称为pankras）中的胰腺肿瘤发生中，Caerulein诱导的胰腺炎会增强恶性进展。除胰腺炎外，突变体KRAS与突变体p53（第二大常见的遗传改变）合作，导致小鼠胰腺癌发展，主要是通过协同调节ERK-MAPK和NF-KB。促炎性可溶性环氧水解酶（SEH）迅速灭活抗炎EET。我们的初步数据表明，1）96％（27/28）和90％（27/30）的人类胰腺腺癌样品分别表现出对SEH和P-C-RAF的明显过表达，以及2）我们的新型Dual C-RAF/SEH抑制剂T-Cupm对pancreatis and PanceReatiation和mpaniratiation pancanins pancanins cant pancanins cant pancanins cant pancanins conteriatiation pancanins contectiation pancanins pancanins contectiation。我们的假设是，C-RAF和SEH在突变KRAS引发并通过胰腺炎或突变体p53增强的胰腺癌中起关键作用。将这两种酶靶向胰腺癌是一种新颖且相关的预防策略。提出了三个具体目的来检验这一假设：1）确定C-RAF/SEH双重抑制剂T-CUPM，SEH抑制剂T- AUCB和RAF抑制剂RAF265/Sorafenib对突变型KRAS引起的和胰腺炎癌（panceReatiation）在pankras小鼠中癌变的影响； 2）确定使用抑制剂或基因基因敲除的阻塞KRAS激活的C-RAF是否抑制了PDX1-KRASG12D-P53R172小鼠中突变体KRAS-P53相互作用和恶性进展； 3）用pankras小鼠中SEH基因敲除方法来确定SEH在胰腺炎和癌变中的作用。拟议的研究的成功不仅会导致我们证明C-RAF和SEH在胰腺癌发生中的作用，而且还可以确立T-CUPM作为抑制胰腺癌发展的新药物的重要性。