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: 9117526
• 负责人: JEAN GAUTIER
• 金额: $ 93.89万
• 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/9117526
• 关键词: Cancer Patient; Clinic; DNA Crosslinking Agent; DNA Damage; DNA Repair; DNA Topoisomerases; Defect; Development; Failure; Genes; Genomic Instability; Health; 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; repaired; targeted treatment; therapy development; 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（由适用提供）：大多数（如果不是所有的肿瘤细胞）都具有基因组不稳定性的迹象，这可能有助于其发育。 DNA修复会打击基因组不稳定性，因此是一种强大的肿瘤抑制机制。编码修复因子的基因中的遗传突变与癌症易感性的显着增加有关，从而确定无法修复DNA损伤原因或促进肿瘤发育。尽管如此，DNA损伤疗法是最广泛使用和最成功的癌症疗法之一。癌细胞的固有基因组不稳定性使它们更容易受到高伤害负担。可以通过靶向对肿瘤细胞至关重要的特定DNA修复模块来探讨这一点。我们将为多个修复途径共有的修复因子建立蛋白质 - 蛋白质相互作用的地图。我们将确定蛋白质 - 蛋白质相互作用，在用DNA拓扑异构酶抑制剂和DNA交联后，这些相互作用被特异性增强或减少。这些不同的监管模块将确定 癌细胞的DNA修复网络将为精确的，有针对性的疗法打开可能性。