Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes

项目 2：识别错构瘤基因突变癌症的代谢脆弱性和靶点

基本信息

批准号：
10715600
负责人：
DAVID J. KWIATKOWSKI
金额：
$ 59.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-24 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715600
关键词：
Alanine Algorithms Back Binding Biochemical Biological Biophysics CRISPR/Cas technology Cell Line Cells Cellular Metabolic Process Clinical Trials Collaborations Computer software Data Dietary Intervention Disease Drosophila genus Drug usage Engineering Enzymes Event FRAP1 gene Family Folliculin Funding Genes Genetic Genetic Crosses Germ-Line Mutation Glycerol Growth Hamartoma Human Human Cell Line Impairment Knock-in Knock-out Lung Neoplasms Malignant Neoplasms Metabolic Metabolic Control Metabolism Methods Molecular Mus Mutation Normal Cell Nuclear Translocation Nutrient Oncogenes PIK3CG gene PTEN gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Protein Kinase Proteins Proteomics Regulation Research Role STK11 gene Sampling Serine Signal Transduction Site Substrate Interaction Substrate Specificity Syndrome TFE3 gene TSC1 gene TSC2 gene Therapeutic Tissues Triose-Phosphate Isomerase Tumor Suppressor Proteins Work biomarker development biomarker driven cancer cell cell growth drug development fly gene network glucose metabolism lipid metabolism loss of function mutation mTOR Signaling Pathway metabolomics mosaic variant mutant new technology new therapeutic target novel novel therapeutics phosphoproteomics pre-clinical rapid growth response transcription factor tumor

项目摘要

Project 2: Abstract The hypothesis guiding this proposal is that mutations in hamartoma syndrome genes (PTEN, LKB1, TSC1, TSC2) dominantly rewire metabolism exposing unique vulnerabilities. The focus of this project is to better understand the molecular and biochemical basis for the metabolic vulnerabilities and provide preclinical data that would support the development of biomarker driven clinical trials to evaluate such drugs in patients with germline or the many tumors containing sporadic mutations in hamartoma syndrome genes. We have decoded the optimal substrate motif for every single mammalian protein kinase in the last funding period and made an algorithm that allows us to decode which kinases are active or inactive in a given biological samples based on unbiased phospho-proteomics. Here we will focus on use of this new method to identify new metabolic enzymes targeted by LKB1-dependent kinases. The specific aims are: 1) Defining critical kinase- substrate interactions deregulated in hamartoma genes in cell lines and tissues; 2) Defining metabolic vulnerabilities deregulated in hamartoma genes in cell lines and tissues; and 3) Defining how AMPK control of TFEB contributes to the survival of hamartoma cells and how to target tumors based on new understanding of this pathway.

项目2：摘要指导该提议的假设是Hamartoma综合征基因的突变（PTEN，LKB1，TSC1， TSC2）主要复兴代谢暴露了独特的漏洞。该项目的重点是更好了解代谢脆弱性的分子和生化基础，并提供临床前数据这将支持生物标志物驱动的临床试验的发展，以评估种系或许多含有零星突变的肿瘤中的Hamartoma综合征基因。我们有在最后一个资金期间，对每个哺乳动物蛋白激酶的最佳底物基序解码制作了一种算法，使我们能够在给定的生物样品中解释哪种激酶是活性或无活性的基于无偏的磷酸蛋白质组学。在这里，我们将专注于使用这种新方法来识别新的由LKB1依赖性激酶靶向的代谢酶。具体目的是：1）定义关键激酶 - 底物相互作用在细胞系和组织中的Hamartoma基因中失调； 2）定义代谢在细胞系和组织中的Hamartoma基因中失去管制的脆弱性； 3）定义AMPK如何控制 TFEB有助于放血瘤细胞的生存以及如何基于对这条路。