In Vivo Metabolic Catastrophe Is Induced By Acute Oncogene Inhibition (PQ #22)

体内代谢灾难是由急性癌基因抑制（PQ

基本信息

批准号：
8384577
负责人：
ANDREI GOGA
金额：
$ 61.1万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8384577
关键词：
Acute Address Anabolism Automobile Driving Breast Cancer Biology Cancer Model Cell Cycle Arrest Cell Death Cell Survival Cells Citric Acid Cycle Cultured Tumor Cells Data Development Event Gene Expression Generations Genes Genetic Glycolysis Goals Histocompatibility Testing Human Image Imaging technology Knowledge Lactate Dehydrogenase Liver neoplasms Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of liver Mammary Neoplasms Mass Spectrum Analysis Metabolic Metabolic Pathway Modeling Neoplasm Metastasis Oncogenes Oncogenic Oxidative Phosphorylation Pathway Analysis Pathway interactions Phenotype Primary Neoplasm Production Proteins Protons Pyruvate Research Signal Pathway Signal Transduction Testing Transgenic Organisms Translating Tumor Tissue Warburg Effect Work base cancer cell cancer regression in vivo innovation insight magnetic resonance spectroscopic imaging meetings metabolomics neoplastic cell novel novel therapeutics pyruvate dehydrogenase tumor

项目摘要

DESCRIPTION (provided by applicant): Despite our rapidly growing understanding of how oncogenes signal, relatively little is known about the underlying mechanisms that cause abrupt cell cycle arrest, cell death and tumor regression upon acutely inactivating an oncogene. This application seeks to address NIH's Provocative Question #22: Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene? We propose that acute inactivation of different oncogenes in diverse tissue types results in a common 'metabolic catastrophe.' Acute inhibition of driver oncogenes results in widespread collapse of tumor-associated metabolic reprograming. The resulting metabolic state of tumor cells can neither supply them with sufficient energy nor metabolic intermediates for anabolism resulting in a state of 'metabolic catastrophe' resulting in tumor cell death and regression of cancers. The aims of the application seek to: 1) Use innovative hyperpolarized 13C-pyruvate imaging to visualize the earliest metabolic events associate with tumor regression. 2) We will perform global gene expression and metabolomic profiling of liver cancers driven by MYC, RAS or MYC and RAS together to define metabolic pathways altered as a consequence of acute oncogene inactivation. 3) We will compare the metabolic consequences of oncogene inactivation in diverse tissue types, including breast, lung and liver tumors to define which oncogene-regulated metabolic pathways are common across different tissue types and driver oncogenes. The overarching goal of these studies is to identify metabolic pathways critical for tumor survival, against which novel therapeutics can be developed. PUBLIC HEALTH RELEVANCE: A major unanswered question in cancer biology is why and how tumors regress when the initiating oncogene is acutely inhibited. This application seeks to answer this question by examining diverse metabolic changes which occur when different oncogenes are acutely inactivated. We will test the effects of inactivating two canonical oncogenes, MYC and RAS and both combined, in breast lung and liver tumor tissues. An innovative approach to study tumor formation and regression will be employed; including novel imaging technology as well as genetic and metabolic profiling of diverse tumor types. We anticipate that knowledge gained from these studies will be rapidly translated to the development of novel therapeutics to target human cancer.

描述（由申请人提供）：尽管我们对Oncogenes信号的迅速了解，但对导致突然的细胞周期停滞，细胞死亡和肿瘤消退的潜在机制相对较少，急性灭活癌基因。该应用程序旨在解决NIH的挑衅性问题＃22：为什么许多癌细胞突然被癌细胞编码的蛋白质时会死亡？我们建议在各种组织类型中急性失活导致常见的“代谢灾难”。急性抑制驱动器癌基因导致肿瘤相关代谢重编程的广泛崩溃。肿瘤细胞的代谢状态既不能为它们提供足够的能量和代谢中间体，从而导致“代谢灾难”，从而导致肿瘤细胞死亡和癌症的消退。该应用程序的目的是：1）使用创新的超极化13C-丙酮酸成像来可视化与肿瘤回归相关的最早的代谢事件。 2）我们将对由MYC，RAS或MYC和RAS驱动的肝癌的全球基因表达和代谢组分析一起定义由于急性致癌基因灭活而改变的代谢途径。 3）我们将比较包括乳腺癌，肺部和肝肿瘤在内的多种组织类型中癌基因灭活的代谢后果，以定义哪种癌基因调节的代谢途径在不同的组织类型和驱动器癌基因中很常见。这些研究的总体目标是确定对肿瘤生存至关重要的代谢途径，可以开发新的治疗疗法。公共卫生相关性：癌症生物学中的一个主要问题是，肿瘤在急性抑制时肿瘤为什么以及如何消退。该应用程序试图通过检查当不同的癌基因被急剧灭活时发生的多种代谢变化来回答这个问题。我们将测试在乳腺肺和肝肿瘤组织中灭活两种典型的癌基因和RAS的效果。将采用一种研究肿瘤形成和回归的创新方法；包括新型成像技术以及各种肿瘤类型的遗传和代谢分析。我们预计从这些研究中获得的知识将迅速转化为针对人类癌症的新型治疗剂的发展。