DNA Repair and Genomic Instability in Cancer Development and Therapy

癌症发展和治疗中的 DNA 修复和基因组不稳定性

• 批准号: 9979776
• 负责人: JEAN GAUTIER
• 金额: $ 88.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979776
• 关键词: Cancer Patient; Clinic; DNA Crosslinking Agent; DNA Damage; DNA Repair; DNA Topoisomerases; Defect; Development; Failure; Genes; Genomic Instability; Inherited; Malignant Neoplasms; Mutation; Pathway interactions; Predisposition; Protein-Protein Interaction Map; Public Health; Radiation therapy; Research; Topoisomerase Inhibitors; Tumor Suppressor Proteins; cancer cell; cancer therapy; chemotherapy; combat; design; neoplastic cell; protein protein interaction; public health relevance; repaired; targeted treatment; tumor

 DESCRIPTION (provided by applicant): Most, if not all tumor cells harbor signs of genomic instability, which can contribute to their development. DNA repair combats genomic instability and thus, is a powerful tumor suppressor mechanism. Inherited mutations in genes encoding for repair factors are associated with significant increases in cancer susceptibility, establishing tha failure to repair DNA damage causes or facilitates tumor development. Nonetheless, DNA damaging therapies are amongst the most widely used and most successful cancer therapies. The inherent genomic instability of cancer cells makes them more vulnerable to a high damage burden. This can be exploited in the clinic by targeting specific DNA repair modules that are uniquely essential for tumor cells. We will build a map of protein-protein interactions for repair factors common to multiple repair pathways. We will identify protein-protein interactions, which are specifically enhanced or reduced following treatment with DNA topoisomerase inhibitors and DNA crosslinkers. These differentially regulated modules will identify potential vulnerabilities in the DNA repair networks of cancer cells and will open the possibility for precise, targeted therapies.

 描述（由申请人提供）：大多数（如果不是全部）肿瘤细胞都具有基因组不稳定的迹象，这有助于其发育，从而对抗基因组不稳定性，因此是编码修复因子的基因中的一种强大的肿瘤抑制机制。与癌症易感性显着增加相关，确定修复 DNA 损伤的失败会导致或促进肿瘤的发展。然而，DNA 损伤疗法是最广泛使用和最成功的癌症疗法之一，癌细胞固有的基因组不稳定性使它们更容易受到攻击。到一个这可以通过针对肿瘤细胞独特必需的特定 DNA 修复模块在临床中加以利用。我们将构建多种修复途径中常见的修复因子的蛋白质-蛋白质相互作用图谱。在使用 DNA 拓扑异构酶抑制剂和 DNA 交联剂处理后，这些相互作用会特别增强或减少，这些差异调节的模块将识别潜在的漏洞。 癌细胞的 DNA 修复网络，将为精确的靶向治疗开辟可能性。