Targeting Cancer-Associated Myofibroblasts by DNA Hypomethylation

通过 DNA 低甲基化靶向癌症相关肌成纤维细胞

基本信息

批准号：
8555378
负责人：
Benjamin Tycko
金额：
$ 20.71万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8555378
关键词：
Address Allografting Biological Assay Cancerous Carcinoma Cells DNA DNA Methylation Data Decitabine Epithelial Epithelial Cells Gene Expression Genes Genetic Growth Human Laboratories Lead Link Liver Fibrosis Maintenance Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of liver Maps Measures Mediating Mesenchymal Stem Cells Methylation Methyltransferase Gene Modeling Molecular Molecular Profiling Mus Myofibroblast Neoplasm Metastasis Nitrosamines Pancreatic carcinoma Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Primary carcinoma of the liver cells Role Stomach Stomach Carcinoma Stromal Cells Testing base cancer therapy cancer type cell stroma chemical carcinogenesis clinically relevant in vivo insight mouse model prevent promoter research study response therapeutic target tumor tumor progression wound

项目摘要

The presence in carcinomas of large numbers of myofibroblasts (MFs) originally suggested the concept of cancer as a non-healing wound, and experiments have now implicated these cells as contributing to cancer growth, invasion and metastasis. Recently our labs (Tycko collaborating with Wang) showed that cancerassociated myofibroblasts (CAFs) in human gastric carcinomas (GCAs) and in a mouse model of GCA have globally reduced DNA methylation and focal gains of promoter methylation, compared to normal MFs in the stomach. We now have substantial unpublished data indicating that these findings of altered DNA methylation in CAFs extend to pancreatic carcinoma (PnCA), and that the demethylating drug decitabine (5aza-dC) has strong anti-tumor activity in a mouse model of PnCA, mediated in part through its effects on the tumor-supporting activity of CAFs and in part via its direct effects on the malignant epithelial cells. To build on these findings we have 4 current objectives - all centered on DNA methylation as a therapeutic target in both the supportive CAFs and malignant epithelial cells of stroma-rich gastrointestinal cancers. First, we will carry out several types of molecular assays to ask whether CAFs accumulate global and genespecific alterations in DNA methylation in pancreatic and hepatocellular carcinomas. Second, we will use mixing/allografting experiments to ask whether the demethylating drug decitabine inhibits the tumorsupporting function of CAFs, and we will profile gene expression and characterize mesenchymal stem cell markers in response to this drug to gain insights to its mechanisms of action against CAFs. Third, we will use in vivo mouse models of PnCA to test whether decitabine, alone and in combination with other agents, can prevent tumor progression and lead to regression of established PnCA tumors. This objective is linked to a Phase 1 clinical trial of decitabine in humans with PnCA, for which we will carry out the laboratory-based pharmacodynamic studies. Our fourth and last objective is to use a genetic strategy in mice to test whether deletion of the maintenance methyltransferase gene Dnmtl, specifically in MFs, can slow or prevent liver fibrosis and cancer in a chemical carcinogenesis model of hepatocellular carcinoma.

大量成肌纤维细胞（MF）的癌中的存在最初提出了癌症是一种非愈合的伤口，实验现已牵涉到这些细胞，这是有助于癌症的生长，入侵和转移。最近，我们的实验室（Tycko与Wang合作）表明癌症相关人胃癌（GCA）和GCA的小鼠模型中的肌纤维细胞（CAF）具有与正常的MF相比胃。现在，我们有大量未发表的数据，表明这些改变了DNA的发现 CAF中的甲基化延伸至胰腺癌（PNCA），并将脱甲基甲基甲基化（5AZA-DC）在PNCA的小鼠模型中具有强大的抗肿瘤活性，部分通过其对 CAF的肿瘤支持活性和部分通过其对恶性上皮细胞的直接影响。为了建立这些发现，我们有4个当前的目标 - 全部以DNA甲基化为中心靶向富基质胃肠道癌的支持性CAF和恶性上皮细胞。首先，我们将进行几种类型的分子测定，以询问CAF是否积累了全球和Genespefific 胰腺和肝细胞癌中DNA甲基化的改变。第二，我们将使用混合/同种试验询问脱甲基化药物解替滨是否抑制肿瘤支持 CAF的功能，我们将介绍基因表达并表征间充质干细胞标记响应这种药物，以了解其针对CAF的作用机理。第三，我们会的使用PNCA的体内小鼠模型来测试解替他单独并与其他药物结合可以防止肿瘤进展并导致已建立的PNCA肿瘤的消退。这个目标是链接的使用PNCA的人类的Decitabine的第一阶段临床试验，我们将进行基于实验室的临床试验药效研究。我们的第四个也是最后一个目标是使用小鼠中的遗传策略来测试是否是否删除维护甲基转移酶基因DNMTL，特别是在MFS中，可以减慢或预防肝脏肝细胞癌的化学癌变模型中的纤维化和癌症。