Activating p53 for colorectal cancer prevention

激活 p53 预防结直肠癌

基本信息

批准号：
9923443
负责人：
Xiangwei Wu
金额：
$ 42.48万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923443
关键词：
Adenomatous Polyposis Coli Affect ApcMin/+ mice Benign Biochemical 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 Foundations Future Genes Genetic Genetic study Genome Histologic Human In Vitro Intervention Intestines Investigational Therapies 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 trial Protein p53 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 experimental study improved inhibitor/antagonist 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 tumorigenesis

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.

项目摘要： p53是一种至关重要的肿瘤抑制剂，可在大多数物种中停止肿瘤发育，并且是最频繁的人类癌中的灭活基因。尽管约有50％的癌症患者含有突变体p53，但许多肿瘤处肿瘤发育的早期阶段保留了野生型p53。在癌症前体中存在野生型p53 病变通过激活p53抑制肿瘤提供了化学预防的绝佳机会进展。 MDM2蛋白是p53的关键负调节剂，在对抗p53中起主要作用通过直接互动。小分子MDM2抑制剂，可阻断MDM2 – P53蛋白 - 蛋白质相互作用将从MDM2释放p53，从而恢复野生型p53的肿瘤抑制功能。我们假设通过阻止MDM2-P53相互作用来增强野生型p53功能使用MDM2抑制剂的前体病变是预防癌症的有效方法。我们建议在apcmin/+小鼠中检验该假设，这是家族性腺瘤性息肉病的模型。如果成功，我们的研究将铺路癌症化学预防的新方法。