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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：
8256911
负责人：
Benjamin Tycko
金额：
$ 20.39万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256911
关键词：
Address Alleles Allografting Apoptosis Biological Assay Cancerous Carcinoma Cell Proliferation Cells Cisplatin Clinical Trials Cytotoxic agent DNA DNA Methylation Data Decitabine Engineering Epithelial Epithelial Cells Fibrosis Gene Expression Genes Genetic Growth Hepatocyte Human Image Instruction Laboratories Lead Link Liver Fibrosis Luciferases Maintenance Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of liver Maps Measurement Measures Mediating Mesenchymal Stem Cells Methylation Methyltransferase Gene Modeling Molecular Molecular Profiling Mus Myofibroblast Neoplasm Metastasis Nitrosamines Pancreatic carcinoma Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase I Clinical Trials Primary carcinoma of the liver cells Role Signal Transduction Stem cells Stomach Stomach Carcinoma Stromal Cells Suppressor Genes Testing Time Transgenic Mice Tumor Volume Ultrasonography Vimentin Work base cancer therapy cancer type cell stroma chemical carcinogenesis clinically relevant demethylation drug testing gemcitabine in vivo inhibitor/antagonist insight luminescence mouse model prevent promoter research study response standard care therapeutic target tumor tumor progression tumorigenesis 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 We now have substantial unpublished data indicating that these findings of altered DNA methylation in CAFs extend to pancreatic carcinoma (PnCA), and that the demethylating drug decitabine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.

癌症中存在大量肌成纤维细胞（MF）最初提出了以下概念：癌症被认为是一种无法愈合的伤口，现在的实验表明这些细胞会导致癌症生长、侵袭和转移。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 小鼠模型中的肌成纤维细胞 (CAF) 与正常 MF 相比，整体 DNA 甲基化和启动子甲基化的局部增益降低胃。我们现在有大量未发表的数据表明这些 DNA 改变的发现 CAF 中的甲基化延伸至胰腺癌 (PnCA)，去甲基化药物地西他滨 (5aza-dC) 在 PnCA 小鼠模型中具有很强的抗肿瘤活性，部分是通过其对 CAF 的肿瘤支持活性部分是通过其对恶性上皮细胞的直接作用实现的。为了以这些发现为基础，我们当前有 4 个目标 - 全部都集中在 DNA 甲基化作为治疗方法靶向富含基质的胃肠癌的支持性 CAF 和恶性上皮细胞。首先，我们将进行几种类型的分子检测，以了解 CAF 是否累积全局和基因特异性胰腺癌和肝细胞癌中 DNA 甲基化的改变。其次，我们将使用混合/同种异体移植实验探讨去甲基化药物地西他滨是否抑制肿瘤支持 CAF 的功能，我们将分析基因表达并表征间充质干细胞标记对该药物的反应，以深入了解其对抗 CAF 的作用机制。第三，我们将使用 PnCA 的体内小鼠模型来测试地西他滨是否单独或与其他药物联合使用，可以阻止肿瘤进展并导致已形成的 PnCA 肿瘤消退。这个目标是相连的地西他滨在患有 PnCA 的人类中进行的 1 期临床试验，为此我们将进行基于实验室的研究药效学研究。我们的第四个也是最后一个目标是在小鼠身上使用遗传策略来测试是否删除维持性甲基转移酶基因 Dnmtl，特别是在 MF 中，可以减缓或预防肝脏损伤肝细胞癌化学致癌模型中的纤维化和癌症。