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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.

项目总结/文摘