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.

项目摘要： 众所周知，DNA损伤反应（DDR）途径的缺陷加速肿瘤发生。 已经致力于靶向有缺陷的DDR途径以改善癌症患者的结果。 这些努力导致FDA批准PARP抑制剂用于治疗携带BRCA 1/2的癌症 基因突变，以及批准用于具有错配修复缺陷的癌症的免疫疗法。而且很多 靶向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， 我们迫切需要了解如何有效地使用这些现有的和新的治疗癌症的方法。 我们现在知道，靶向DDR途径和/或DDR缺陷不仅影响内在肿瘤增殖， 也改变了肿瘤微环境的相互作用。因此，我们正在将DDR研究从体外扩展到体内。 vivo设置。在这个项目中，我们将确定几个重要的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分离，以进一步 阐明这些DDR基因和途径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DDR缺陷。我们最近在体内CRISPR筛选方面的成功为我们提供了 有机会探索靶向DDR途径和DDR缺陷的途径，用于体内癌症治疗。我们 我预计从这些研究中获得的知识将有助于我们设计更好的癌症治疗策略 患者