Targeting non-homologous end joining in cancer therapy

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题，03-CA-103试剂，用于快速筛查人类肿瘤细胞的DNA修复和/或复制缺陷。DNA修复缺陷在肿瘤中很常见，参与双链断裂(DSB)修复的基因功能缺失等位基因可导致遗传性癌症易感综合征。双链断裂是最危险的DNA损伤形式，因为它们的错误修复会导致粗大的染色体排列并促进癌症。双链断裂的修复主要通过两种途径之一：同源重组(HR)和非同源末端连接(NHEJ)。多聚ADP核糖聚合酶(PARP)抑制剂用于增敏HR缺陷的肿瘤细胞(如缺乏BRCA1或BRCA2的肿瘤细胞)的最新进展突显了在这些细胞中靶向修复途径而不是HR所固有的治疗协同效应。我们相信，PARP抑制剂并不是唯一一类显示出这种协同作用的试剂。我们认为，在HR缺陷的细胞中抑制NHEJ可能是癌症治疗的另一个靶点。为此，我们开发了一种新的、快速的、高灵敏度的哺乳动物细胞中NHEJ的检测方法。我们建议使用这一方法和我们开发的现有HR分析方法来实现以下三个目标：目的1.通过对促进NHEJ的基因进行siRNA筛选，寻找调控哺乳动物NHEJ的新基因。目的2.通过对抑制哺乳动物NHEJ的化合物进行化学筛选，以确定抑制哺乳动物NHEJ的新疗法。目的3.建立一种快速、灵敏、定量的检测人肿瘤细胞同源重组缺陷的方法。 公共卫生相关性：双链断裂(DSB)修复缺陷在人类癌症中很常见，为人类癌症的治疗提供了一个令人兴奋的潜在新靶点。我们实验室开发的新工具将使我们能够快速筛选人类基因组中调节DSB修复的新基因。我们将使用相同的技术来识别针对DSB修复进行治疗的新分子，并快速评估人类癌症的DSB修复缺陷。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-CA-103 Reagents for rapid screening of human tumor cells for defects in DNA repair and/or replication. Defective DNA repair is common in tumors, and loss-of-function alleles of genes involved in double strand break (DSB) repair can cause hereditary cancer predisposition syndromes. DSBs are the most dangerous form of DNA damage, since their misrepair can cause gross chromosomal arrangements and promote cancer. DSBs are repaired by one of two major pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). The recent development of poly(ADP ribose) polymerase (PARP) inhibitors to sensitize tumor cells defective for HR (such as those lacking BRCA1 or BRCA2) has highlighted the therapeutic synergy inherent in targeting repair pathways other than HR in these cells. We believe that PARP inhibitors are not the only class of reagent that will show such synergy. We propose that NHEJ inhibition in cells defective for HR may represent an additional target for cancer therapy. To this end, we have developed a novel, rapid and highly sensitive assay for NHEJ in mammalian cells. We proposed to use this and existing HR assays, developed by us, for the following three Aims: Aim 1. By conducting a siRNA screen for genes that promote NHEJ, to identify new genes that regulate mammalian NHEJ. Aim 2. By conducting a chemical screen for compounds that inhibit mammalian NHEJ, to identify new therapeutics that inhibit mammalian NHEJ. Aim 3. To develop a rapid, sensitive and quantitative assay for screening of human tumor cells for defects in homologous recombination. PUBLIC HEALTH RELEVANCE: Defects in double strand break (DSB) repair are common in human cancers, and offer an exciting potential new target for therapy of human cancer. New tools developed in our laboratory will allow us to rapidly screen the human genome for new genes that regulate DSB repair. We will use the same technology to identify new molecules that target DSB repair for therapy, and to rapidly assess human cancers for defective DSB repair.