Chemoprevention of colon cancer by targeting the Wnt/beta-catenin pathway

通过靶向 Wnt/β-连环蛋白途径化学预防结肠癌

基本信息

批准号：
9249395
负责人：
Zigang Dong
金额：
$ 34.88万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249395
关键词：
Adenomatous Polyposis Coli Adverse effects Affinity Animal Experiments Binding Binding Proteins Binding Sites Biological Assay Biological Models Cancer Cell Growth Cancer Etiology Cell Nucleus Cell model Cells Cessation of life Chemoprevention Chemopreventive Agent Colon Colon Carcinoma Colonic Adenoma Colorectal Cancer Complex Computational Biology Computer Simulation Crystallization Cytoplasm Data Databases Development Docking Effectiveness Enzymes Event Exhibits Gene Targeting Genes Genetic Transcription Germ-Line Mutation Glycogen (Starch) Synthase Growth Inborn Genetic Diseases Intestines Lead Lesion Malignant Neoplasms Mediating Mutation Nuclear Oncogenic Pathway interactions Patients Pharmaceutical Chemistry Polyps Proteins Rectum Role Signal Pathway Signal Transduction Structure Study models System TCF Transcription Factor Technology Testing Tissues Transgenic Mice Tumor Suppressor Genes WNT Signaling Pathway Xenograft Model Xenograft procedure adenoma attenuation beta catenin beta-Casein cancer cell carcinogenesis casein kinase I cell transformation cell type colon carcinogenesis colon tumorigenesis design in vivo inhibitor/antagonist migration mouse model multicatalytic endopeptidase complex mutant neoplastic novel public health relevance screening small molecule small molecule inhibitor supercomputer targeted agent tumor

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most common cause of cancer death in the USA. Germline mutations in the apc tumor suppressor gene, one of the key players in the development of CRC and an important component in the Wnt/beta-catenin signaling pathway, are responsible for familial adenomatous polyposis (FAP). Mutations that result in constitutive activation of the Wnt/ß-catenin signaling pathway can lead to colon cancer. Wnt(s) have diverse roles in regulating cell fate, proliferation, migration, and death. beta-Catenin is highly expressed in many cancer cell types and promotes growth and tumor formation. Elevated beta-catenin activity in carcinogenesis model systems and neoplastic tissues suggests that this enzyme is a valid target for chemoprevention. By using computational biology with BlueGene/L and GPU supercomputers, we have identified/synthesized several small molecule inhibitors of beta-catenin that are highly effective or have good potential to suppress colon carcinogenesis. In this application, we propose to use state of the art technologies to continue to identify, characterize, test and validate novel, nontoxic small molecule inhibitors of beta-catenin. Our approaches include determination of binding, binding affinities, identification of the specific binding sites, and examining the resulting structural changes by computational simulation using our supercomputer systems. We will validate the effectiveness of these inhibitors by performing protein binding assays, cell transformation assays and in vivo animal experiments, including xenograft models and the AOM-induced colon cancer and APCMin mouse models. Through these studies, we will develop more effective agents targeting beta-catenin with fewer side effects for the chemoprevention of colon cancer.

描述（由适用提供）：大肠癌（CRC）是美国癌症死亡的第三大原因。 APC肿瘤抑制基因的种系突变，CRC发展的主要参与者之一，以及Wnt/beta-catenin信号传导途径中的重要组成部分，是农场腺瘤性息肉病（FAP）的原因。导致Wnt/ß-catenin信号通路的组成型激活的突变会导致结肠癌。 Wnt（S）在控制细胞脂肪，增殖，迁移和死亡方面具有潜水员的作用。 β-catenin在许多癌细胞类型中高度表达，并促进生长和肿瘤形成。癌变模型系统中的β-catenin活性升高，肿瘤组织表明该酶是化学预防的有效靶标。通过将计算生物学与Bluegene/L和GPU超级计算机一起使用，我们已经确定/合成了β-catenin的几种小分子抑制剂，它们非常有效或具有抑制结肠癌发生的良好潜力。在此应用中，我们建议使用艺术技术的状态继续识别，表征，测试和验证β-catenin的新颖的无毒小分子抑制剂。我们的方法包括确定结合，结合亲和力，对特定结合位点的识别以及使用我们的超级计算机系统通过计算模拟来检查所得的结构变化。我们将通过执行蛋白质结合测定，细胞转化测定和体内动物实验，包括异种移植模型以及AOM诱导的结肠癌和APCMIN小鼠模型来验证这些抑制剂的有效性。通过这些研究，我们将开发针对β-catenin的更有效的药物，其副作用较少，以减少结肠癌的化学预防。