Metabolic and epigenetic reprogramming in cyclin E high ovarian cancer

项目摘要/摘要 这项MPI提案的最终目标是解决对乙酰辅酶A作用的认识上的根本差距 代谢重编程调节Cyclin 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~20%的患者的治疗产生重大影响 Cyclin E高表达的高级别浆液性卵巢癌(HGSOC)患者对 由于精通同源重组(HR)介导的DNA修复，新兴的PARP抑制剂疗法。 这项研究计划侧重于评估实验和机械确定的时空 乙酰辅酶A对组蛋白超乙酰化的代谢重编程及HR介导的DNA增强 细胞周期蛋白E升高的HGSOC患者联合新生的修复和该通路是否可以靶向 PARP抑制剂治疗，以获得合成致死性和持续的治疗反应。建议进行的研究 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-High细胞中上调， 乙酰辅酶A在胞浆和胞核中受空间调控，细胞周期蛋白E-High表现为高乙酰化 已知的与HR修复有关的组蛋白。根据这些数据，我们将探索两个最重要的科学 目的：1)定量剖析细胞周期蛋白E高的HGSOC中乙酰辅酶A代谢重编程及其贡献 以及2)确定乙酰辅酶A介导的表观遗传改变是否起作用 卵巢肿瘤的发生和治疗反应。这项提议的科学目标的完成不会 仅对乙酰辅酶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 AXIS在卵巢肿瘤发生过程中，但也将建立以此为目标的轴作为一种改进治疗的策略 周期蛋白E水平高的HGSOC患者的预后。拟议的研究具有很高的影响力，因为 这些通路的机械性基础有可能改变HGSOC患者的管理 随着PARP抑制剂被开发用于多种癌症类型，研究将具有深远的意义 发现抑制HR介导的DNA修复和发展未来癌症的新策略的意义 治疗策略适用于广泛的患者。

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.