Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes
Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes
批准号:
10715600
负责人:
DAVID J. KWIATKOWSKI
金额:
$59.15万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
未结题
起止时间:
2007-04-24 至 2028-07-31
关键词:
AlanineAlgorithmsBackBindingBiochemicalBiologicalBiophysicsCRISPR/Cas technologyCell LineCellsCellular Metabolic ProcessClinical TrialsCollaborationsComputer softwareDataDietary InterventionDiseaseDrosophila genusDrug usageEngineeringEnzymesEventFRAP1 geneFamilyFolliculinFundingGenesGeneticGenetic CrossesGerm-Line MutationGlycerolGrowthHamartomaHumanHuman Cell LineImpairmentKnock-inKnock-outLung NeoplasmsMalignant NeoplasmsMetabolicMetabolic ControlMetabolismMethodsMolecularMusMutationNormal CellNuclear TranslocationNutrientOncogenesPIK3CG genePTEN genePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPhosphotransferasesPlayProtein KinaseProteinsProteomicsRegulationResearchRoleSTK11 geneSamplingSerineSignal TransductionSiteSubstrate InteractionSubstrate SpecificitySyndromeTFE3 geneTSC1 geneTSC2 geneTherapeuticTissuesTriose-Phosphate IsomeraseTumor Suppressor ProteinsWorkbiomarker developmentbiomarker drivencancer cellcell growthdrug developmentflygene networkglucose metabolismlipid metabolismloss of function mutationmTOR Signaling Pathwaymetabolomicsmosaic variantmutantnew technologynew therapeutic targetnovelnovel therapeuticsphosphoproteomicspre-clinicalrapid growthresponsetranscription factortumor
中文摘要
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Integrative molecular dissection of acquired resistance to PD1/PD-L1 blockade in localized and metastatic urothelial carcinoma
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批准号:10218294
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项目类别:
-
资助金额:$47.63万
-
财政年份:2021
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Genetics of LAM
-
批准号:10318188
-
项目类别:
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资助金额:$44.97万
-
财政年份:2020
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负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Genetics of LAM
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批准号:10524041
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项目类别:
-
资助金额:$44.97万
-
财政年份:2020
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负责人:DAVID J. KWIATKOWSKI
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依托单位:
Integrated analyses of cancers harboring STK11 vs. TSC1/2 vs. PTEN Loss
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批准号:8567633
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项目类别:
-
资助金额:$44.14万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
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依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
-
批准号:8549956
-
项目类别:
-
资助金额:$167.3万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
-
批准号:8719031
-
项目类别:
-
资助金额:$172.72万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Integrated analyses of cancers harboring STK11 vs. TSC1/2 vs. PTEN Loss
-
批准号:8719034
-
项目类别:
-
资助金额:$46.33万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Core A: Administration
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批准号:10715602
-
项目类别:
-
资助金额:$8.4万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
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批准号:7191898
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项目类别:
-
资助金额:$155.08万
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财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
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依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
-
批准号:9120313
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项目类别:
-
资助金额:$178.16万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Project 1: Identifying new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation
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批准号:10715599
-
项目类别:
-
资助金额:$53.08万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Core B: Mass Spectrometry, proteomics, metabolmics and lipidomics
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批准号:10715603
-
项目类别:
-
资助金额:$16.97万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
-
批准号:8070486
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项目类别:
-
资助金额:$155.83万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Administrative Core
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批准号:8567634
-
项目类别:
-
资助金额:$3.29万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Administrative Core
-
批准号:9120331
-
项目类别:
-
资助金额:$3.06万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
-
批准号:8915499
-
项目类别:
-
资助金额:$178.15万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Project 3: Identifying transcriptional driver genes and targeting transcription in TSC
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批准号:10715601
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项目类别:
-
资助金额:$79.24万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
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依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
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批准号:10715598
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项目类别:
-
资助金额:$216.84万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
-
依托单位:
Integrated analyses of cancers harboring STK11 vs. TSC1/2 vs. PTEN Loss
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批准号:8915508
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项目类别:
-
资助金额:$47.51万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
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依托单位:
Molecular Pathogenesis of the Hamartoma Syndromes
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批准号:8413956
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项目类别:
-
资助金额:$191.15万
-
财政年份:2007
-
负责人:DAVID J. KWIATKOWSKI
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依托单位:
海外基金