Understanding synthetic lethality of ATR inhibitors with DDR dysregulation common in ovarian cancer

关键词：健康长寿DNA损伤反应：DNA修复和细胞周期检查点，ATR生物标志物开发的翻译研究卵巢癌新疗法的患者分层本项目旨在通过利用DNA损伤反应（DDR）中的缺陷，探索Vertex制药公司开发的ATR抑制剂在卵巢癌中的治疗潜力。ATR通过向细胞周期检查点和修复发送DNA损伤信号，是DDR的关键。DDR的某些缺陷赋予了对ATR抑制的敏感性。这些缺陷在卵巢癌中很常见，卵巢癌是女性癌症死亡的第五大常见原因。该项目将涉及一组卵巢癌细胞系的细胞毒性研究，DDR基因的敲低，机制研究，以确定为什么一些DDR缺陷赋予对ATR抑制的敏感性，以及使用来自患者的卵巢癌原代培养物进行转化研究。培训相关的生物化学和分子技术，科学的方法和智力的严谨性。该项目的部分工作将在工业赞助商Vertex的实验室进行。

Key words:Living a long and Healthy lifeDNA damage response: DNA repair and cell cycle checkpoints, ATRTranslational studies for Biomarker development Patient stratification to new treatments for ovarian cancerThis project aims to explore the therapeutic potential of an ATR inhibitor, developed at Vertex Pharmaceuticals, in ovarian cancer through exploitation of defects in the DNA damage response (DDR). ATR is key to the DDR by signalling DNA damage to cell cycle checkpoints and repair. Certain defects in the DDR confer sensitivity to ATR inhibition. Many of these defects are common in ovarian cancer, the 5th most frequent cause of cancer death in women. The project will involve cytotoxicity studies in a panel of ovarian cancer cell lines, knockdown of DDR genes, mechanistic studies to determine why some DDR defects confer sensitivity to ATR inhibition and translational studies using primary cultures of ovarian cancer from patients. Training in relevant biochemical and molecular techniques, the scientific method and intellectual rigor will be given. Parts of the project will be undertaken at Vertex, the industrial sponsor's laboratories.