Targeting G-quadruplex DNA to overcome resistance to PARP inhibitors

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，这两种癌症通常是BRCA2缺乏的。然而，在临床中已经观察到对PARP抑制剂的耐药性，这增加了对替代brca2选择性治疗的需求。g -四重体配体最近成为潜在的治疗工具，在BRCA2基因缺陷背景下显示出更高的毒性，在奥拉帕尼耐药癌症中也保持其活性。然而，缺乏对PARP活性、NAD+代谢和gfour - plex形成之间的基本生物学联系的理解，这阻碍了对这一治疗途径的进一步研究。在这个项目中，我们建议结合合成、代谢组学和基因组学来揭示PARP活性与g -四重体形成之间的串扰。这项研究将揭示g -四重体形成和NAD+代谢的基本机制，为下一代治疗parp耐药癌症患者的药物设计提供一个平台。

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.