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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：
10170288
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/10170288
关键词：
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 Familial Adenomatous Polyposis Syndrome Foundations Future Genes Genetic Genetic study Genome Histologic Human In Vitro Intervention 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 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 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.

项目概要： p53是一种重要的肿瘤抑制因子，在大多数物种中可以阻止肿瘤的发展，人类癌症中的失活基因虽然约50%的癌症患者携带突变型p53，但许多肿瘤在肿瘤发展的早期保留野生型p53。野生型p53在癌症前体中的存在通过激活p53抑制肿瘤的化学预防，进展MDM 2蛋白是p53的关键负调节因子，在拮抗p53中起主要作用通过直接互动。阻断MDM 2-p53蛋白-蛋白的小分子MDM 2抑制剂相互作用将从MDM 2中释放p53，从而恢复野生型p53的肿瘤抑制功能。我们假设通过阻断MDM 2-p53相互作用增强野生型p53的功能，使用MDM 2抑制剂的前驱病变是预防癌症的有效方法。我们建议在ApcMin/+小鼠（一种家族性腺瘤性息肉病模型）中检验这一假设。如果成功，我们的研究将为癌症化学预防的新途径。