DNA Repair and Genomic Instability in Cancer Development and Therapy

 描述(由申请人提供)：大多数，如果不是所有的肿瘤细胞都有基因组不稳定的迹象，这可能有助于它们的发展。DNA修复可以对抗基因组的不稳定性，因此是一种强大的肿瘤抑制机制。编码修复因子的基因的遗传突变与癌症易感性的显著增加有关，从而确立了未能修复DNA损伤导致或促进肿瘤发展的可能性。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。癌细胞与生俱来的基因组不稳定性使它们更容易受到高损伤负担的影响。通过靶向特定的DNA修复模块，这一点可以在临床上加以利用，这些模块对肿瘤细胞是唯一必不可少的。我们将构建修复因子的蛋白质-蛋白质相互作用图，这些修复因子是多条修复途径共同的。我们将确定蛋白质之间的相互作用，这种相互作用在用DNA拓扑异构酶抑制剂和DNA交联剂处理后特别增强或减少。这些不同监管的模块将识别 癌细胞的DNA修复网络，将为精确的、有针对性的治疗打开可能性。

 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.