Targeting non-homologous end joining in cancer therapy

描述（由申请人提供）：该申请涉及广泛的挑战领域（03）生物标志物发现和验证以及特定的挑战主题，用于快速筛选人类肿瘤细胞DNA修复和/或复制缺陷的03- ca -103试剂。DNA修复缺陷在肿瘤中很常见，参与双链断裂（DSB）修复的基因的功能等位基因缺失可导致遗传性癌症易感性综合征。dsb是最危险的DNA损伤形式，因为它们的错误修复会导致总体染色体排列并促进癌症。dsb的修复主要有两种途径：同源重组（HR）和非同源末端连接（NHEJ）。最近开发的聚（ADP核糖）聚合酶（PARP）抑制剂对HR缺陷的肿瘤细胞（如缺乏BRCA1或BRCA2的肿瘤细胞）敏感，突出了靶向这些细胞中HR以外的修复途径固有的治疗协同作用。我们相信PARP抑制剂并不是唯一一类能显示这种协同作用的试剂。我们提出，在HR缺陷细胞中抑制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NHEJ检测方法。我们建议使用该方法和我们开发的现有HR测定法，用于以下三个目的：通过对促进NHEJ的基因进行siRNA筛选，以确定调节哺乳动物NHEJ的新基因。目标2。通过对抑制哺乳动物NHEJ的化合物进行化学筛选，确定抑制哺乳动物NHEJ的新疗法。目标3。目的：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。

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.