Targeting pancreatic cancer energy metabolism, tumor growth, and metastasis

针对胰腺癌能量代谢、肿瘤生长和转移

基本信息

批准号：
9281690
负责人：
Michael B Dwinell
金额：
$ 51.58万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281690
关键词：
Adenocarcinoma Cell Biochemical Bioenergetics Biological Assay Cations Cell Culture Techniques Cell Death Cell Proliferation Cells Cellular Metabolic Process Citric Acid Cycle Clinic Collaborations Cytolysis Diagnosis Disease Distant Drug Targeting Energy Metabolism FRAP1 gene Generations Genus Hippocampus Glucose Glutamine Glycolysis Goals Growth Health Human Image Imaging Techniques In Vitro Investigation Magnetic Resonance Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Measures Metabolic Metabolism Metformin Mitochondria Modeling Neoplasm Metastasis Normal Cell Nutrient Oxidative Phosphorylation Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Perception Pharmaceutical Preparations Phenotype Production Public Health Publishing Pyruvate Research Role SCID Mice Scientist Severity of illness Signal Pathway Signal Transduction Survival Rate Testing Time Tissues Translating Warburg Effect Western Blotting Work Xenograft procedure aerobic glycolysis analog antitumor agent base bioluminescence imaging cancer cell cancer therapy cell growth cell motility chemotherapy conventional therapy cytotoxicity design drug efficacy drug testing experimental study extracellular gemcitabine improved in vivo in vivo bioluminescence imaging inhibitor/antagonist innovation metabolomics migration mitochondrial metabolism neoplastic cell novel therapeutic intervention novel therapeutics pancreatic cancer cells pre-clinical preclinical efficacy public health relevance standard of care trafficking tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Emerging research in cancer therapy is focused on exploiting the biochemical differences between cancer cell and normal cell metabolism. The Warburg effect is a fundamental change in many malignant cancer cells and is the shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. The common perception is that this metabolic reprogramming provides the cellular energy required for unregulated cell growth, invasion, and metastasis. Human pancreatic ductal adenocarcinoma (PDAC) is an incurable and highly aggressive human cancer. The median survival of the 75-80% of patients with malignant PDAC at the time of initial diagnosis is 6-months. Standard chemotherapy with the cytolytic drug gemcitabine provides a slight survival benefit. Thus, there is an unmistakable and critical unmet need for new therapies to treat patients with pancreatic cancer. The overall goal of this project is to develop new therapeutic approaches to inhibit PDAC malignancy. The significance of the proposed work lies in the use of relatively nontoxic mitochondria-targeted cationic drugs in combination with glycolytic and glutaminolytic energy metabolism inhibitors to decrease pancreatic cancer cell proliferation and metastasis. The overarching hypothesis is that a combination of glycolytic, glutaminolytic, and/or mitochondrial metabolism inhibitors with standard therapies will deplete ATP, decrease energy sensing, proliferation, and migration in vitro, and inhibit aerobic glycolysis and human PDAC tumor growth and metastasis in vivo. Studies in Aim 1 will use innovative high-throughput and mass spectroscopy-based metabolomics approach to investigate bioenergetic changes in glycolysis, tricarboxylic acid cycle, and glutaminolysis in human primary PDAC cells treated with mitochondria-targeted cationic agents, and/or inhibitors of energy metabolism. Aim 2 will use cell culture approaches to define the role for bioenergetic metabolism inhibitors in activating energy regulatory signaling pathways and altering PDAC growth, invasion, and migration. Aim 3 will use preclinical hyperpolarized magnetic resonance and bioluminescence imaging techniques to screen the in vivo efficacy of targeted drugs that inhibit energy metabolism, alone or in combination with traditional chemotherapy to mitigate PDAC growth and metastasis. The overall impact of the proposed work is two-fold: First, it will advance our understanding of the role of metabolism, energetics, and energy sensing in pancreatic cancer malignancy and second it will engender the design and testing of drugs that stifle energy production and which may ultimately be translated to the clinic.

描述（由申请人提供）：癌症治疗中的新兴研究重点是利用癌细胞和正常细胞代谢之间的生化差异。 Warburg效应是许多恶性癌细胞中的根本变化，是能量代谢从氧化磷酸化向有氧糖酵解的转变。普遍的看法是，这种代谢重编程提供了细胞生长，浸润和转移所需的细胞能量。人胰腺导管腺癌（PDAC）是一种无法治愈且高度侵略性的人类癌症。最初诊断时，75-80％的恶性PDAC患者的中位生存期为6个月。用细胞溶剂吉西他滨进行标准化学疗法可提供略有生存优势。因此，对于治疗胰腺癌患者的新疗法有明确且至关重要的未满足需求。该项目的总体目标是开发新的治疗方法来抑制PDAC恶性肿瘤。提出的工作的重要性在于使用相对无毒的线粒体靶向阳离子药物与糖酵解和谷氨酰胺分解能量代谢抑制剂结合使用，以减少胰腺癌细胞的增殖和转移。 The overarching hypothesis is that a combination of glycolytic, glutaminolytic, and/or mitochondrial metabolism inhibitors with standard therapies will deplete ATP, decrease energy sensing, proliferation, and migration in vitro, and inhibit aerobic glycolysis and human PDAC tumor growth and metastasis in vivo. AIM 1中的研究将使用创新的高通量和质谱代谢组学方法来研究用线粒体靶向阳离子阳离子阳离子剂，/或能量能量代理的人类原代PDAC细胞中糖酵解，三羧酸周期和谷氨酰胺分解的生物能变化。 AIM 2将使用细胞培养方法来定义生物能代谢抑制剂在激活能量调节信号通路和改变PDAC生长，侵袭和迁移中的作用。 AIM 3将使用临床前超极化磁共振和生物发光成像技术来筛选靶向药物的体内疗效，这些药物单独或与传统的化学疗法结合抑制能量代谢，以减轻PDAC生长并转移。拟议工作的总体影响是两个方面：首先，它将促进我们对胰腺癌恶性肿瘤中新陈代谢，能量感和能量感测的作用的理解，其次，它将引起扼杀能源生产的药物的设计和测试，这些药物最终可能会转化为临床。