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Activating p53 for colorectal cancer prevention

激活 p53 预防结直肠癌

基本信息

批准号：
10643714
负责人：
Xiangwei Wu
金额：
$ 37.51万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10643714
关键词：
Affect ApcMin/+ mice Benign Biochemical Breeding Cancer Etiology Cancer Patient Cardiovascular system Cessation of life Chemoprevention Chemopreventive Agent Colon Colonic Polyps Colorectal Cancer Data Development Dose Drug Kinetics Effectiveness Elephants Excision Familial Adenomatous Polyposis Syndrome Foundations Future Genes Genetic Genetic study Genome Histologic Human In Vitro Intervention Investigation Left Lesion MDM2 gene Malignant Neoplasms Mediating Medical Research Modeling Mus Mutant Strains Mice Mutation Mutation Detection Non-Steroidal Anti-Inflammatory Agents Normal tissue morphology Nude Mice Operative Surgical Procedures Oral Patients Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Play Polyps Prevention strategy Prevention trial Reporting Role Small Intestines Solid TP53 gene Testing Toxic effect Tumor Suppression Tumor Suppressor Proteins Tumor Tissue Tumor stage United States Upper digestive tract structure adenoma cancer chemoprevention cancer clinical trial cancer prevention cancer therapy cell growth cohort colon growth colon tumorigenesis colorectal cancer prevention conditional mutant design efficacy evaluation experimental study improved inhibitor intestinal tumorigenesis lifetime risk mouse model mutant novel strategies preclinical toxicity prevent protein protein interaction response side effect small molecule tumor tumor growth tumor initiation tumor progression tumor xenograft

项目摘要

PROJECT SUMMARY: p53 is a crucial tumor suppressor that stops tumor development in most species and is the most frequently inactivated gene in human cancers. Although about 50% of cancer patients harbor mutant p53, many tumors at early stages of tumor development retain wild type p53. The presence of wild-type p53 in cancer precursor lesions presents an excellent opportunity for chemoprevention by activating p53 to suppress tumor progression. The MDM2 protein is a key negative regulator of p53 and plays a primary role in antagonizing p53 through direct interaction. Small molecule MDM2 inhibitors that block the MDM2–p53 protein–protein interaction would liberate p53 from MDM2, thereby restoring the tumor suppressor function of wild-type p53. We hypothesize that enhancement of wild-type p53 functions by blocking MDM2-p53 interaction in precursor lesions using MDM2 inhibitor is an effective approach for cancer prevention. We propose to test this hypothesis in ApcMin/+ mice, a model for familial adenomatous polyposis. If succeed, our study will pave a new way for cancer chemoprevention.

项目总结: