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

• 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
• 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

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 指导这一建议的假设是错构瘤综合征基因（PTEN，LKB 1，TSC 1， TSC 2）主要重新连接代谢，暴露出独特的脆弱性。该项目的重点是更好地 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，以评估这些药物在患者中的作用。 生殖系或许多肿瘤含有零星突变的错构瘤综合征基因。我们有 在上一个资助期内，解码了每种哺乳动物蛋白激酶的最佳底物基序， 我做了一个算法，使我们能够解码哪些激酶是活跃的或不活跃的，在一个给定的生物样本 基于无偏磷酸蛋白质组学。在这里，我们将重点介绍使用这种新方法来识别新的 LKB 1依赖性激酶靶向的代谢酶。具体目标是：1）定义关键激酶- 细胞系和组织中错构瘤基因中底物相互作用失调; 2）定义代谢 在细胞系和组织中错构瘤基因中失调的脆弱性;和3）定义AMPK如何控制错构瘤基因的表达。 TFEB有助于错构瘤细胞的存活，以及如何基于对肿瘤的新理解靶向肿瘤。 这条路。