Role of Altered Nutrient Metabolism in Pancreatic Cancer

营养代谢改变在胰腺癌中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，是胰腺的主要形式癌症。随着发病率的增长，它目前是美国癌症死亡的第三大原因。尽管在理解其生物学，遗传学和危险因素方面取得了进步，但PDAC仍保持预后极低，5年生存率仅为10％。这主要源于其晚期诊断，积极的性质和对疗法的抵抗力。因此，迫切需要新颖的治疗方法。靶向PDAC中的代谢改变的目标已有十多年来一直进行了广泛的研究领域。一个然而，对于大多数抗肿瘤代谢策略而言，主要障碍是有毒副作用的高风险，鉴于代谢途径在维持正常组织稳态中的基本作用。这确实是靶向癌症中多胺的情况。多胺是小的，高阳性的分子参与细胞生长和存活的多个基本过程，包括核酸的合成染色质结构，基因转录和mRNA翻译的修饰。多胺水平为包括PDAC在内的许多癌症中显着增加。以前的反肿瘤策略着重于多胺合成，鸟氨酸脱羧酶（ODC1）的限速酶的药理抑制作用几乎没有成功，部分原因是在较高的药物剂量下损害正常组织的风险。该项目确定旨在验证胰腺癌的依赖性，无论是在体外培养细胞和体内小鼠中的依赖性，多胺前体鸟氨酸的合成的一种非常规的方式，特别是从谷氨酰胺通过鸟氨酸氨基转移酶（燕麦）;将其与精氨酸的大多数成年正常组织中的合成通过精氨酸酶（ARG）活性。它还旨在确定介导的潜在关键参与者 PDAC中主要的致癌驱动器Kras的代谢途径，并表征下游效应与正常胰腺相比细胞。 PDAC的高依赖性，而不是正常组织对谷氨酰胺的从头鸟嘌呤合成提供了一个有吸引力的治疗窗口，用于治疗毒性最小的胰腺癌患者。