Exploring DNA damage response pathways as targets for cancer therapy

探索 DNA 损伤反应途径作为癌症治疗的目标

• 批准号: 10515484
• 负责人: Junjie Chen
• 金额: $ 58.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515484
• 关键词: Affect; BRCA mutations; CRISPR screen; Cancer Patient; Cell Cycle Checkpoint; Cell Proliferation; Clinical Trials; DNA Damage; DNA Repair; Defect; Development; Gene Proteins; Genes; Genomic Instability; Goals; Immune Targeting; In Vitro; Knowledge; Mismatch Repair Deficiency; Mutation; Pathway interactions; anticancer treatment; cancer immunotherapy; cancer therapy; design; gene repair; immune checkpoint; improved outcome; in vivo; inhibitor; novel therapeutics; response; success; targeted cancer therapy; treatment strategy; tumor; tumor microenvironment; tumorigenesis

Project Summary: It is well established that defects in DNA damage response (DDR) pathways accelerate tumorigenesis. Significant efforts have been devoted to target defective DDR pathways to improve outcome for cancer patients. These efforts led to the FDA’s approval of PARP inhibitors for the treatment of cancers carrying BRCA1/2 mutations and also the approval of immunotherapy for cancers with mismatch repair deficiency. Moreover, many inhibitors targeting DNA repair and/or cell cycle checkpoints have also entered clinical trials. Thus, there is an urgent need to understand how to effectively use these existing and new therapies for cancer treatment. We now know that targeting DDR pathways and/or DDR defects not only affect intrinsic tumor proliferation, but also change tumor-microenvironment interactions. Thus, we are expanding our DDR studies from in vitro to in vivo settings. In this project, we will determine mechanistically how several essential DDR genes/proteins control cell proliferation and DNA damage repair. We plan to establish separation of function mutations to further elucidate the key roles of these DDR genes and pathways both in vitro and in vivo. Additionally, we will investigate DDR defects in cancer therapy in vivo. Our recent success with in vivo CRISPR screens provides us an opportunity to explore avenues to target DDR pathways and DDR defects for cancer treatment in vivo. We anticipate that knowledge gained from these studies will help us design better treatment strategies for cancer patients.

项目概要： 众所周知，DNA 损伤反应 (DDR) 途径的缺陷会加速肿瘤发生。 人们致力于针对有缺陷的 DDR 通路以改善癌症患者的预后。 这些努力导致 FDA 批准 PARP 抑制剂用于治疗携带 BRCA1/2 的癌症 突变以及对错配修复缺陷癌症的免疫疗法的批准。而且，许多 针对 DNA 修复和/或细胞周期检查点的抑制剂也已进入临床试验。因此，有一个 迫切需要了解如何有效地利用这些现有的和新的疗法来治疗癌症。 我们现在知道，针对 DDR 通路和/或 DDR 缺陷不仅会影响内在的肿瘤增殖，还会影响 也改变肿瘤与微环境的相互作用。因此，我们正在将 DDR 研究从体外扩展到体内 体内设置。在这个项目中，我们将从机制上确定几个必需的 DDR 基因/蛋白质如何控制 细胞增殖和DNA损伤修复。我们计划建立功能突变的分离，以进一步 阐明这些 DDR 基因和通路在体外和体内的关键作用。此外，我们将 研究体内癌症治疗中的 DDR 缺陷。我们最近在体内 CRISPR 筛选方面取得的成功为我们提供了 这是一个探索靶向 DDR 通路和 DDR 缺陷以进行体内癌症治疗的途径的机会。我们 预计从这些研究中获得的知识将帮助我们设计更好的癌症治疗策略 患者。