Targeting the ATR pathway in p53-deficient cancers

靶向 p53 缺陷癌症中的 ATR 通路

基本信息

批准号：
8300806
负责人：
FRED BUNZ
金额：
$ 34.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-13 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300806
关键词：
Activities of Daily Living Aftercare Antineoplastic Agents Binding Biochemical Bypass CDK2 gene Cell Cycle Cell Line Cell Survival Cells Chemosensitization Cisplatin Clinic Clinical Combined Modality Therapy Complex Cyclin-Dependent Kinases DNA Damage DNA Replication Damage DNA biosynthesis Data Defect Drug Combinations Drug Delivery Systems Effectiveness Elements Epitopes Exhibits Genes Genetic Genomics Goals Growth Holoenzymes Homeostasis Human In Vitro Ionizing radiation Knock-out Malignant Neoplasms Maps Mediating Mediator of activation protein Methods Mus Mutation Pathway interactions Pharmaceutical Preparations Pharmacogenetics Phase Phosphotransferases Play Proteins Regulation Role S Phase Signal Transduction Site Small Interfering RNA Somatic Cell Stimulus Stress TP53 gene Testing Therapeutic Agents Tissues anti-cancer therapeutic base cancer cell cell growth chemotherapeutic agent combinatorial design homologous recombination in vivo insight mutant neoplastic cell protein protein interaction response tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Cancer cells that harbor inactivating p53 mutations exhibit checkpoint defects and impaired DNA damage responses. Because p53 mutations are prevalent in many common cancers, strategies that would exploit these defects are predicted to have significant clinical impact. This proposal is focused on the ATR pathway, which has recently emerged as a critical modulator of p53-deficient cancer cell survival in response to therapeutic agents. The ATR kinase holoenzyme is activated by DNA damage and DNA replication stress, and is therefore responsive to many of the anticancer agents currently in use. Recent studies have revealed new mechanisms by which ATR is controlled. These insights provide new opportunities to target this pathway. This proposed project employs genetic and biochemical methods to study the protein-protein interactions that define the competent ATR complex, and the effects of common chemotherapeutic agents on complex formation. The effectiveness of targeting distinct upstream and downstream components of the ATR pathway, including Cdk2 and Chk1, will be comparatively evaluated in vitro and in vivo. In a coordinated effort, a pharmacogenetic array of approved drugs will be screened to identify new ATR activators. Human somatic cells with targeted genetic alterations will be used to identify new drug/target combinations. A focused effort will be made to screen for genes that promote survival in response to cisplatin, an anticancer drug recently found to induce distinct survival pathways in cells that are deficient for p53. The long-term objectives of this project are to reveal basic mechanisms of ATR regulation, new drug targets, and new strategies for generating synthetic lethality in p53-deficient human cancer cells.

描述（由申请人提供）：伴有灭活p53突变的癌细胞表现出检查点缺陷和DNA损伤反应受损。由于p53突变在许多常见的癌症中普遍存在，因此预计将利用这些缺陷的策略具有重大的临床影响。该提案的重点是ATR途径，该途径最近已成为p53缺陷型癌细胞存活的关键调节剂，响应治疗剂。 ATR激酶全酶被DNA损伤和DNA复制应力激活，因此对当前使用的许多抗癌剂有反应。最近的研究揭示了对ATR控制的新机制。这些见解为针对这一途径提供了新的机会。该提出的项目采用遗传和生化方法来研究定义有效ATR复合物的蛋白质蛋白质相互作用，以及常见化学治疗剂对复杂形成的影响。靶向包括CDK2和CHK1在内的ATR途径的不同上游和下游组件的有效性将在体外和体内进行相对评估。在协调的工作中，将筛选一系列批准的药物以鉴定新的ATR激活剂。具有靶向遗传改变的人类体细胞将用于鉴定新药/靶标组合。将集中精力为筛选促进对顺铂的生存的基因筛查，这是一种抗癌药物，该药物最近发现诱导p53不足的细胞中的不同生存途径。该项目的长期目标是揭示ATR调控，新药物靶标的基本机制以及在p53缺陷型人类癌细胞中产生合成致死性的新策略。