Targeting G-quadruplex DNA to overcome resistance to PARP inhibitors

靶向 G-四链体 DNA 以克服对 PARP 抑制剂的耐药性

• 批准号: 2596469
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2596469
• 关键词: Targeting; quadruplex; DNA; overcome; resistance

PARP inhibitors such as Olaparib have revolutionised treatment of ovarian and breast cancers, whichare typically BRCA2 deficient. However, resistance to PARP inhibitors has been already observed inthe clinic, rising the need of alternative BRCA2-selective therapies. G-quadruplex ligands haverecently emerged as potential therapeutic tools that displayed increased toxicity in BRCA2 deficientgenetic backgrounds, retaining their activity also in Olaparib resistant cancers. However, there is alack of understanding of the fundamental biology linking PARP activity, NAD+ metabolism and Gquadruplex formation, which hampers to investigate further this therapeutic avenue. In this project, we propose to combine synthesis, metabolomics and genomics to unravel the crosstalk between PARP activity and G-quadruplex formation. This study, will shed light on the fundamentalmechanisms linking G-quadruplex formation and NAD+ metabolism, providing a platform for therational design of the next generation of drugs to treat PARP-resistant cancer patients.

PARP抑制剂如奥拉帕尼已经彻底改变了卵巢癌和乳腺癌的治疗方法，这些癌症通常是BRCA 2缺乏的。然而，在临床上已经观察到对PARP抑制剂的耐药性，这增加了对替代BRCA 2选择性治疗的需求。G-四链体配体最近成为潜在的治疗工具，在BRCA 2缺陷遗传背景中显示出增加的毒性，在奥拉帕尼耐药的癌症中也保留了它们的活性。然而，对PARP活性、NAD+代谢和Gquadruplex形成的基础生物学缺乏了解，这阻碍了进一步研究这种治疗途径。在这个项目中，我们建议结合联合收割机合成，代谢组学和基因组学来解开PARP活性和G-四链体形成之间的串扰。本研究将揭示G-四链体形成和NAD+代谢的基本机制，为合理设计下一代治疗PARP耐药癌症患者的药物提供平台。