Metabolic and epigenetic reprogramming in cyclin E high ovarian cancer

细胞周期蛋白 E 高卵巢癌的代谢和表观遗传重编程

• 批准号: 10182029
• 负责人: Katherine Marie Aird
• 金额: $ 57.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182029
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Address; Affect; CCNE1 gene; Cancer Patient; Cell Cycle Progression; Cell Nucleus; Cells; Chromatin; Clinical; Cytoplasm; DNA Damage; DNA Repair; DNA Repair Enzymes; Data; Dependence; Development; Disease; Enzymes; Epigenetic Process; Event; Future; Genetic Transcription; Glucose; Goals; Histone Acetylation; Histones; Human; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mediating; Metabolic; Metabolism; Modeling; Molecular; Oncogenes; Oncogenic; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Proliferating; Proteins; Publishing; Relaxation; Research; Resistance; Role; Serous; Testing; Therapeutic; base; cancer cell; cancer type; clinically relevant; epigenome; histone acetyltransferase; homologous recombination; improved; inhibitor/antagonist; insight; new therapeutic target; novel strategies; novel therapeutic intervention; overexpression; patient population; recombinational repair; recruit; replication stress; response; spatiotemporal; standard of care; therapy outcome; treatment response; treatment strategy; tumor; tumorigenesis; tumorigenic

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.

项目摘要/摘要 该MPI提案的最终目标是解决有关乙酰辅酶A的知识的根本差距 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会对约20％的治疗产生重大影响 高浆液卵巢癌（HGSOC）患有高细胞周期蛋白E表达的患者的抗性 由于具有同源重组（HR）介导的DNA修复的熟练程度，新兴的PARP抑制剂疗法。 该研究计划重点是通过实验和机械学确定时空的评估 乙酰辅酶A对组蛋白高乙酰化的代谢重编程和HR介导的DNA的增强 维修以及该途径是否可以针对细胞周期蛋白E-HIGH HGSOC患者，并结合出现 PARP抑制剂疗法获得合成的致死性和持续的治疗反应。提出的研究 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进行空间调节，细胞周期蛋白E高细胞显示高乙酰化 已知参与HR修复的组蛋白。与这些数据一致，我们将探索两个总体科学 目的：1）定量剖析细胞周期蛋白E高HGSOC及其贡献的乙酰-COA代谢重编程 进行HR介导的DNA修复； 2）确定乙酰-COA介导的表观遗传学变化是否有助于 卵巢肿瘤发生和治疗反应。该提议的科学目的的完成将不会 仅提供对乙酰-COA介导的代谢性景观之间的相互作用的新机械见解 卵巢肿瘤发生期间的轴，但也将建立针对该轴作为改善治疗的策略 HGSOC高细胞周期蛋白E的结果。拟议的研究具有很高的影响，因为 这些途径的机械基础有可能改变HGSOC患者的管理 随着高细胞周期蛋白E的高度，作为许多癌症类型的PARP抑制剂，研究将具有深远的影响 确定抑制HR介导的DNA修复并发展未来癌症的新型策略的意义 各种患者的治疗策略。