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：
8478065
负责人：
FRED BUNZ
金额：
$ 31.99万
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/8478065
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 Targeting 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）：含有失活 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 突变在许多常见癌症中普遍存在，因此利用这些缺陷的策略预计将产生重大的临床影响。该提案的重点是 ATR 通路，该通路最近已成为 p53 缺陷型癌细胞响应治疗药物存活的关键调节剂。 ATR 激酶全酶由 DNA 损伤和 DNA 复制应激激活，因此对目前使用的许多抗癌药物有反应。最近的研究揭示了控制 ATR 的新机制。这些见解为瞄准这一途径提供了新的机会。该拟议项目采用遗传和生化方法来研究定义 ATR 复合物的蛋白质-蛋白质相互作用，以及常见化疗药物对复合物形成的影响。将在体外和体内比较评估针对 ATR 途径的不同上游和下游组件（包括 Cdk2 和 Chk1）的有效性。在协调一致的努力下，将对一系列已批准药物进行药物遗传学筛选，以确定新的 ATR 激活剂。具有靶向基因改变的人类体细胞将用于识别新的药物/靶标组合。我们将集中精力筛选能够响应顺铂而促进存活的基因，顺铂是一种抗癌药物，最近发现它可以在缺乏 p53 的细胞中诱导不同的存活途径。该项目的长期目标是揭示 ATR 调节的基本机制、新的药物靶点以及在 p53 缺陷的人类癌细胞中产生合成致死作用的新策略。