A new kinase inhibitor for glioblastoma
A new kinase inhibitor for glioblastoma
批准号:
10019480
负责人:
Raymond Daniel Blind
金额:
$18.49万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-17 至 2022-08-31
关键词:
1-Phosphatidylinositol 3-KinaseAgarAntineoplastic AgentsAstrocytesBackBasic ScienceBinding SitesBrainCancer ModelCell Culture TechniquesCell LineCell NucleusCell modelCellsChemicalsChronicClinical TrialsCollaborationsComplementDataDevelopmentDrug DesignDrug TargetingEndocrineEndocrine System DiseasesEngraftmentFutureG1/S ArrestGenomeGlial Fibrillary Acidic ProteinGlioblastomaGliomaGoalsGrantGrowthHumanIndustrializationInositolInvestmentsKnock-outKnockout MiceLettersMalignant NeoplasmsMembraneMusMutationNatureNuclearOncogenicPTEN genePaperPathway interactionsPharmaceutical PreparationsPharmacologic SubstancePhenocopyPhenotypePhosphatidylinositide 3-Kinase InhibitorPhosphatidylinositol 4,5-DiphosphatePhosphotransferasesPhysiologicalPoint MutationProblem SolvingProgram DevelopmentPublic HealthResearchResistanceResolutionRoleScientistSignal PathwaySignal TransductionStructureStudy modelsSystemTestingTherapeuticTissuesTumor Suppressor ProteinsVirusXenograft procedurebasecancer cellcancer therapycell growthchemical geneticsdrug candidatedruggable targeteffective therapyexperimental studyglioma cell linehuman tissuein vivoinhibitor/antagonistinositol polyphosphate multikinasekinase inhibitormembermouse modelmutanttooltumor
中文摘要
文摘:
英文摘要
Abstract:
The tumor suppressor PTEN counteracts Class 1 PI3-kinase functions in membranes, leading to
the massive kinase inhibitor development efforts currently attempting to counteract loss of PTEN in
human tumors. However, we discovered a new PTEN signaling pathway in the nucleus that is
completely decoupled from Class 1 PI3-kinases. The “decoupling” is important for anti-cancer drug
design because if a tumor is growing due to loss of nuclear PTEN, Class 1 PI3-kinase inhibitors
would be ineffective against those tumors. Indeed, PI3-kinase inhibitors often fail to rescue loss of
PTEN function in clinical trials, for incompletely understood reasons. Further, this new PTEN
pathway has never been studied in any model of cancer, as we discovered it fortuitously while
examining endocrine disorders. The kinase opposing PTEN in the nuclear pathway is a poorly
characterized member of the inositol kinase superfamily called “Inositol Polyphosphate Multikinase”
(IPMK). IPMK is a nuclear PIP2-kinase with ubiquitous expression in all human tissues, structurally
unrelated to Class 1 PI3-kinases. Alfred Yung showed certain glioblastoma cell lines halted growth
when complemented with nuclear, not cytoplasmic PTEN2. Based on the nuclear pathway, we
hypothesized IPMK knockout might mimic nuclear PTEN complementation in these cells. Indeed,
preliminary data show CRSIPR knockout of IPMK phenocopies nuclear PTEN complementation in
these cells. Wild type but not kinase-dead IPMK rescues the phenotype, suggesting an IPMK
inhibitor could be an effective therapy. This grant develops a chemical genetic mutant of IPMK to
determine if IPMK inhibitors would be effective in glioblastoma. Future projects will use
physiologically relevant mouse models to establish IPMK as a validated target for full scale
industrial kinase inhibitor efforts.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
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批准号:10372324
-
项目类别:
-
资助金额:$29.42万
-
财政年份:2022
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负责人:Raymond Daniel Blind
-
依托单位:
Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
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批准号:10772905
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项目类别:
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资助金额:$18.84万
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财政年份:2022
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负责人:Raymond Daniel Blind
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依托单位:
IPMK function in chromatin
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批准号:10350670
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项目类别:
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资助金额:$37.4万
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财政年份:2020
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负责人:Raymond Daniel Blind
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依托单位:
Full-length LRH-1 structural regulation
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批准号:10034145
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项目类别:
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资助金额:$34.6万
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财政年份:2020
-
负责人:Raymond Daniel Blind
-
依托单位:
Full-length LRH-1 structural regulation
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批准号:10245137
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项目类别:
-
资助金额:$34.6万
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财政年份:2020
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负责人:Raymond Daniel Blind
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依托单位:
IPMK function in chromatin
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批准号:9973484
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项目类别:
-
资助金额:$37.4万
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财政年份:2020
-
负责人:Raymond Daniel Blind
-
依托单位:
IPMK function in chromatin
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批准号:10598523
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项目类别:
-
资助金额:$37.4万
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财政年份:2020
-
负责人:Raymond Daniel Blind
-
依托单位:
Full-length LRH-1 structural regulation
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批准号:10697397
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项目类别:
-
资助金额:$34.6万
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财政年份:2020
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负责人:Raymond Daniel Blind
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依托单位:
Cancer cell signaling through lipids complexed to proteins
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批准号:8543686
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项目类别:
-
资助金额:$11.22万
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财政年份:2012
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负责人:Raymond Daniel Blind
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依托单位:
Cancer cell signaling through lipids complexed to proteins
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批准号:8708521
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项目类别:
-
资助金额:$11.22万
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财政年份:2012
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负责人:Raymond Daniel Blind
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依托单位:
Cancer cell signaling through lipids complexed to proteins
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批准号:8426060
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项目类别:
-
资助金额:$11.22万
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财政年份:2012
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负责人:Raymond Daniel Blind
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依托单位:
国内基金
海外基金
Cd(II)在NH2-Agar/PSS双网络水凝胶上的吸附行为及资源化工艺研究
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批准号:51708204
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项目类别:青年科学基金项目
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资助金额:25.0万元
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批准年份:2017
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负责人:周贵寅
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依托单位: