Role of Altered Nutrient Metabolism in Pancreatic Cancer

营养代谢改变在胰腺癌中的作用

• 批准号: 10598613
• 负责人: Nada Y. Kalaany
• 金额: $ 51.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598613
• 关键词: Acetylation; Address; Adult; Affect; Amines; Area; Arginine; Automobile Driving; Binding; Biological Assay; Biology; Cancer Etiology; Cancer Patient; Cell Survival; Cell physiology; Cells; Cessation of life; ChIP-seq; Charge; Chromatin; Chromatin Structure; Cultured Cells; Data; Databases; Dependence; Diagnosis; Dose; Doxycycline; Ductal Epithelial Cell; Enhancers; Enzyme Inhibition; Enzymes; Epigenetic Process; Extinction; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genetically Engineered Mouse; Glutamine; Goals; Growth; Histone H3; Histones; Homeostasis; Human; In Vitro; Incidence; Infusion procedures; Intercellular Fluid; Intervention; Investigation; KRAS2 gene; Knock-out; Label; Lysine; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mus; Nature; Nitrogen; Normal Cell; Normal tissue morphology; Nucleic Acids; Nucleotides; Oncogenic; Ornithine; Ornithine Decarboxylase; Ornithine-oxo-acid aminotransferase; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Pathway interactions; Pharmaceutical Preparations; Polyamines; Production; Prognosis; Proteins; Putrescine; Risk; Risk Factors; Role; Source; Spermidine; Spermine; Survival Rate; Therapeutic; Tissues; Toxic effect; Transcriptional Activation; Translations; Transplantation; Transposase; Withdrawal; Work; arginase; cell growth; chromatin modification; effective therapy; experimental study; high risk; in vivo; infancy; knock-down; mRNA Translation; mouse model; neoplastic cell; novel; novel therapeutic intervention; nutrient metabolism; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pharmacologic; side effect; stem; success; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor growth; tumorigenic

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and is the major form of pancreatic cancer. With an incidence on the rise, it currently ranks as the third leading cause of cancer death in the US. Despite recent advances in the understanding of its biology, genetics and risk factors, PDAC has maintained extremely poor prognosis, with a 5-year survival rate of only 10%. This mainly stems from its late diagnosis, aggressive nature and resistance to therapies. Thus, novel therapeutic approaches are urgently needed. Targeting altered metabolism in PDAC has been an area of extensive investigation for over a decade now. A major hurdle however, for most anti-tumor metabolic strategies, is the high risk of toxic side effects, given the essential roles of metabolic pathways in the maintenance of normal tissue homeostasis. This has indeed been the case for targeting polyamines in cancers. Polyamines are small, highly positively charged molecules involved in multiple fundamental processes of cell growth and survival, including the synthesis of nucleic acids, modifications of chromatin structure, gene transcription and mRNA translation. Polyamine levels are significantly increased in many cancers, including PDAC. Prior anti-tumor strategies focused on pharmacological inhibition of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC1) with little success, partially due to risk of harming normal tissues at higher drug doses. This project identifies and aims at validating a dependency of pancreatic cancer, both in cultured cells in vitro and in mice in vivo, on an unconventional way for the synthesis of the polyamine precursor ornithine, specifically from glutamine via ornithine aminotransferase (OAT); this is compared to its synthesis in most adult normal tissues from arginine via arginase (ARG) activity. It also aims at identifying potential key players mediating the induction of this metabolic pathway by KRAS, the main oncogenic driver in PDAC, and to characterize the downstream effects of polyamines on transcriptional activation and gene expression in PDAC cells compared to normal pancreatic cells. The high dependency of PDAC, but not normal tissues on de novo ornithine synthesis from glutamine provides an attractive therapeutic window for treating pancreatic cancer patients with minimal toxicity.

项目概要/摘要 胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，是胰腺癌的主要形式 癌症。随着发病率的上升，它目前已成为美国癌症死亡的第三大原因。 尽管最近对其生物学、遗传学和风险因素的理解取得了进展，但 PDAC 仍然坚持认为 预后极差，5年生存率仅为10%。这主要源于其诊断较晚， 攻击性和对治疗的抵抗力。因此，迫切需要新的治疗方法。 十多年来，针对 PDAC 代谢改变的研究一直是广泛研究的领域。一个 然而，对于大多数抗肿瘤代谢策略来说，主要障碍是毒副作用的高风险，因为 代谢途径在维持正常组织稳态中的重要作用。这确实已经 以多胺治疗癌症为例。多胺是带高正电荷的小分子 参与细胞生长和生存的多个基本过程，包括核酸的合成， 染色质结构、基因转录和 mRNA 翻译的修饰。多胺含量为 在包括 PDAC 在内的许多癌症中显着增加。先前的抗肿瘤策略主要集中在 多胺合成限速酶鸟氨酸脱羧酶 (ODC1) 的药理学抑制 收效甚微，部分原因是较高药物剂量有损害正常组织的风险。该项目确定 旨在验证体外培养细胞和小鼠体内胰腺癌对胰腺癌的依赖性 合成多胺前体鸟氨酸的非常规方法，特别是通过谷氨酰胺合成 鸟氨酸转氨酶（OAT）；与大多数成人正常组织中精氨酸的合成相比 通过精氨酸酶（ARG）活性。它还旨在确定调解这一诱导的潜在关键参与者 KRAS（PDAC 中的主要致癌驱动因素）的代谢途径，并表征下游效应 与正常胰腺相比，多胺对 PDAC 细胞转录激活和基因表达的影响 细胞。 PDAC（而非正常组织）高度依赖谷氨酰胺从头合成鸟氨酸 为治疗胰腺癌患者提供了一个有吸引力的治疗窗口，且毒性最小。