权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeted Approach for Prevention and Therapy of Colorectal Cancer

结直肠癌的靶向预防和治疗方法

基本信息

批准号：
8688968
负责人：
Vincent W Yang
金额：
$ 33.15万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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/8688968
关键词：
Antineoplastic Agents Apoptosis Bioavailable Cancer Etiology Cancer cell line Cell Cycle Cell Proliferation Cessation of life Colon Carcinoma Colorectal Colorectal Cancer Data Development Disease Drug Compounding Drug Kinetics Epithelial Epithelial Cell Proliferation Epithelial Cells Germ-Line Mutation Goals Human Impairment In Vitro Intestinal Neoplasms Intestines KRAS2 gene Knowledge Lead Life Link Mediating Modification Molecular Morbidity - disease rate Mus Mutation Neoplasm Metastasis Oncogenic Pathway interactions Pattern Phosphotransferases Play Prevention Prevention therapy Property Research Proposals Role Signal Pathway Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Therapeutic Uses Tissues Transgenic Mice Tumor Suppressor Genes United States Up-Regulation Xenograft Model analog base cancer cell cancer therapy carcinogenesis cellular targeting crypt cell drug metabolism improved in vivo inhibitor/antagonist intestinal crypt migration mortality mouse model novel novel therapeutics overexpression physical property preclinical efficacy prevent public health relevance research study scaffold screening small molecule tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the leading causes of cancer morbidity and mortality in the United States. The multistep progression from normal intestinal epithelial tissue to metastatic neoplasm results from impairment of multiple regulatory mechanisms involving critical signaling pathways that regulate normal patterns of proliferation, differentiation, migration, and apoptosis. Among these, the Wnt and RAS signaling pathways play crucial roles in governing intestinal cell proliferation and are the most frequently perturbed in colorectal cancer. Despite this knowledge, few therapeutic strategies have been developed to specifically target components of these particular pathways, and none have gained FDA approval. Our group has identified Kr¿ppel-like factor 5 (KLF5) as an important regulator of intestinal epithelial cell proliferation that is frequently overexpressed during intestinal tumorigenesis. Recently, we have linked KLF5 to both the RAS and Wnt signaling pathways in colorectal carcinogenesis. Our group has also observed that reduction in KLF5 expression leads to reduced intestinal tumor formation in mice harboring a germline mutation in the tumor suppressor gene, APC, a crucial component of the Wnt pathway, or combined APC and KRAS mutations. Using an ultrahigh-throughput screening (uHTS) approach to identify novel lead compounds with potential therapeutic benefits by targeting KLF5 expression, followed by structure-activity studies on the resultant hits, we identified a novel small molecule, ML264, which potently and selectively blocks KLF5 expression in and decreases proliferation of colorectal cancer cell lines. We propose to further characterize the mechanisms by which ML264 inhibits KLF5 expression and evaluate its efficacy as a therapeutic agent for colorectal cancer. The Long-Term Goal of this research proposal is to develop and characterize novel therapeutic agents for the prevention and/or treatment of colorectal cancer. Based on our results we propose the Central Hypothesis that the compound ML264 prevents colorectal cancer development and progression by decreasing KLF5 expression in vivo. To test this hypothesis we propose three Specific Aims: 1) To investigate the mechanism by which ML264 regulates KLF5 expression in CRC cells; 2) To evaluate the preclinical efficacy of compound ML264 in preventing colon cancer formation in mouse models of colorectal cancer; and 3) To generate optimized analogs of ML264 with fully appropriate pharmacokinetic properties for anticancer therapy. The experiments proposed in this application will provide a definitive refinement of the structure and function of ML264 and its optimized analogs. The intent of this effort is to obtain well-tolerated, long-lived bioavailable compounds suitable for therapeutic use in colorectal cancer.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症发病率和死亡率的主要原因之一。从正常肠上皮组织到转移性肿瘤的多步骤进展是由于多种调节机制的损害，包括调节正常增殖、分化、迁移和凋亡模式的关键信号通路。其中，Wnt和RAS信号通路在控制肠细胞增殖中起着至关重要的作用，也是最常受到干扰的