Exploring DNA damage response pathways as targets for cancer therapy

项目总结： 众所周知，DNA损伤反应(DDR)通路的缺陷会加速肿瘤的发生。 已经致力于针对有缺陷的DDR通路来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治疗的批准。此外，许多人 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将这些现有的和新的疗法用于癌症治疗。 我们现在知道，靶向DDR通路和/或DDR缺陷不仅影响固有的肿瘤增殖，而且 也改变了肿瘤与微环境的相互作用。因此，我们正在将我们的DDR研究从体外扩展到 VIVO设置。在这个项目中，我们将机械地确定几个必需的DDR基因/蛋白质是如何控制的 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，我们还将 研究体内肿瘤治疗中的DDR缺陷。我们最近在活体CRISPR筛查方面的成功为我们提供了 有机会探索针对体内癌症治疗的DDR通路和DDR缺陷的途径。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 病人。

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.