Metabolic and epigenetic reprogramming in cyclin E high ovarian cancer

项目总结/摘要 这项mPI提案的最终目标是解决乙酰辅酶A作用知识的根本空白 代谢重编程在调节细胞周期蛋白E高卵巢癌DNA损伤反应、转化和 对治疗的反应。这些研究的结果可能对约20%的患者的治疗产生重大影响。 高级别浆液性卵巢癌（HGSOC）患者的细胞周期蛋白E高表达，这是耐药 由于在同源重组（HR）介导的DNA修复中的熟练性，新兴的PARP抑制剂疗法。 这项研究计划的重点是评估实验和机械确定时空 乙酰辅酶A对组蛋白超乙酰化的代谢重编程和HR介导的DNA的增强 修复以及该途径是否可以在细胞周期蛋白E高HGSOC患者中靶向， PARP抑制剂治疗，以获得合成致死性和持续的治疗反应。拟议的研究 是基于我们的初步发现，即葡萄糖衍生的乙酰辅酶A在细胞周期蛋白E-高细胞中上调， 乙酰辅酶A在细胞质和细胞核中受到空间调控，细胞周期蛋白E高的细胞显示乙酰化过度 已知参与HR修复的组蛋白。根据这些数据，我们将探讨两个总体科学 目的：1）定量分析细胞周期蛋白E高水平HGSOC中乙酰辅酶A代谢重编程及其作用 HR介导的DNA修复; 2）确定乙酰辅酶A介导的表观遗传变化是否有助于 与卵巢肿瘤发生和治疗反应有关。完成这项建议的科学目标将不会 仅为乙酰辅酶A介导的代谢-表观遗传之间的相互作用提供了新的机制见解， 轴在卵巢肿瘤发生过程中，但也将建立靶向这一轴作为一种策略，以提高治疗 具有高细胞周期蛋白E的HGSOC患者的结局。这项研究具有很大的影响力，因为 这些途径的机制基础有可能改变HGSOC患者的管理 高细胞周期蛋白E。由于PARP抑制剂正在开发用于许多癌症类型，因此研究将具有深远的意义。 识别抑制HR介导的DNA修复和发展未来癌症的新策略的意义 为广大患者提供治疗策略。

Project Summary/Abstract The ultimate goal of this mPI proposal is to address a fundamental gap in knowledge on the role of acetyl-CoA metabolic reprogramming in regulating cyclin E-high ovarian cancer DNA damage response, transformation, and response to therapy. The results from these studies could have a significant impact on the treatment of the ~20% of high grade serous ovarian cancer (HGSOC) patients with high cyclin E expression, which are resistant to emerging PARP inhibitor therapies due to proficiency in homologous recombination (HR)-mediated DNA repair. This research plan focuses on assessing the experimentally and mechanistically determining the spaciotemporal metabolic reprogramming of acetyl-CoA on histone hyperacetylation and enhancement of HR-mediated DNA repair and whether this pathway can be targeted in cyclin E-high HGSOC patients in combination with emerging PARP inhibitor therapies to obtain a synthetic lethality and sustained therapeutic response. The proposed studies are based on our preliminary findings that glucose-derived acetyl-CoA is upregulated in cyclin E-high cells, acetyl-CoA is spatially regulated in the cytoplasm and nucleus, and cyclin E-high cells display hyperacetylation of histones known to be involved in HR repair. In line with these data, we will explore two overarching scientific aims: 1) quantitatively dissect acetyl-CoA metabolic reprogramming in cyclin E-high HGSOC and its contribution to HR-mediated DNA repair; and 2) to determine whether acetyl-CoA mediated epigenetic changes contributes to ovarian tumorigenesis and therapeutic response. The completion of the scientific aims of this proposal will not only provide new mechanistic insights into the interplay between the acetyl-CoA-mediated metabolic-epigenetic axis during ovarian tumorigenesis, but will also establish targeting this axis as a strategy to improve therapeutic outcome for HGSOC patients with high cyclin E. The proposed research is of high impact because the mechanistic underpinning of these pathways has the potential to transform the management of HGSOC patients with high cyclin E. As PARP inhibitors are being developed for many cancer types, studies will have far-reaching implications for identifying novel strategies to inhibit HR-mediated DNA repair and develop future cancer therapeutics strategies for a wide range of patients.