Project 3: The AMPK Autophagy Pathway as a Metabolic Liability in Pancratic Ductal Adenocarcinoma
项目 3:AMPK 自噬途径作为胰腺导管腺癌的代谢负担
基本信息
- 批准号:10629065
- 负责人:
- 金额:$ 46.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-06 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenocarcinomaAffectAlanineAttenuatedAutomobile DrivingAutophagocytosisAutophagosomeBiochemicalBiological AvailabilityCell CompartmentationCell NucleusCell SurvivalCell physiologyCellsCharacteristicsChemoresistanceChloroquineClinicClinicalCollaborationsDNA DamageDesmoplasticDevelopmentDiseaseDisease ProgressionDuct (organ) structureEnzymesEpigenetic ProcessEpithelial CellsEpitheliumFRAP1 geneFibroblastsGene ExpressionGeneticGenetic TranscriptionGenetically Engineered MouseGrowthHDAC3 geneHistone DeacetylaseHumanKPC modelKnowledgeLesionMEK inhibitionMEKsMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMediatingMediatorMetabolicMetabolic stressMetabolismModalityMusMutationMyelogenousNormal CellNutrientNutrient availabilityOrganellesOrganoidsPancreas TransplantationPancreatic Ductal AdenocarcinomaParacrine CommunicationPathway interactionsPerformancePharmaceutical PreparationsPhenotypePhosphorylationPhosphotransferasesPopulationProteinsRecyclingRegulationReporterReportingResearchResistanceRoleSignal TransductionSourceStressStromal CellsTherapeuticToxic effectTranslatingUp-RegulationVascularizationWorkXenograft procedureantagonistcheckpoint inhibitionchemotherapydefined contributioneffective therapyefficacy evaluationepigenetic regulationexperimental studyin vivoinhibition of autophagyinhibitorkinase inhibitormTOR inhibitionmouse modelneoplastic cellnovelnovel strategiespancreatic ductal adenocarcinoma modelpancreatic neoplasmpharmacologicprogramsresponsesynergismtargeted treatmenttherapeutic targettherapy resistanttooltranscriptional reprogrammingtreatment responsetreatment strategytumortumor growthtumor microenvironmenttumor progression
项目摘要
PROJECT SUMMARY – Project 3: Autophagy
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest forms of cancer with few effective therapies.
The poor performance of current treatments is partly due to metabolic adaptations in both the tumor and stromal
compartments, such as the recycling of proteins and organelles through increased autophagy. As a hallmark of
PDA, autophagy provides a key source of nutrients in the restrictive tumor microenvironment (TME).
Accumulating evidence also implicates the autophagy program as a critical mediator of resistance to numerous
therapeutics, including chemotherapy, MEK inhibitors, and immune checkpoint inhibition. Foundational research
from the Shaw group decoded key biochemical steps involved in the initiation of autophagy, including upstream
regulation of AMPK and its downstream activation of ULK1 and ULK2, the kinases that drive autophagosome
formation. More recent work from the Shaw group has also revealed that AMPK can block the translocation of
Class II HDACs to the nucleus. Despites these advances, the specific roles of AMPK in autophagy control and
epigenetic regulation have never been investigated in pancreatic cancer. Moreover, while autophagy has
emerged as an attractive therapeutic target in pancreatic cancer, efforts to translate this to the clinic have been
hindered by a lack of autophagy-specific inhibitors, with only broad lysosomotropic agents like chloroquine
available for study. To address this gap, the lab has developed novel, bioavailable inhibitors of ULK1 and ULK2,
two of only three druggable enzymes specific to the autophagy pathway. These inhibitors provide critical tools
with which to dissect the contributions of autophagy to PDA growth and form the basis for a new approach for
overcoming therapeutic resistance in this deadly disease. Here, experiments proposed in Aim 1 will define when
and where different facets of AMPK signaling and autophagy are activated during disease progression in the
autochthonous mouse KPC model of PDA. In collaboration with Project 1, conditional deletions of AMPK or its
downstream targets ULK1/2 and HDAC3 will be used to evaluate their contribution to metabolic adaptations
driving tumor growth and epigenetic changes mediating tumor cellular functions. In addition, the contribution of
AMPK pathway components in supporting PDA resistance to chemotherapeutics and targeted therapies will be
dissected. In Aim 2, the roles of canonical and noncanonical autophagy in non-cell autonomous support of
pancreatic tumor growth will be delineated by comparing stromal deletion of ULK1/2 and ATG7. In addition,
experiments will dissect cell-specific requirements for autophagy within the fibroblast and myeloid compartments
in supporting PDA therapeutic resistance. In Aim 3, the Shaw lab’s novel, bioavailable ULK inhibitor will be used
to determine how selective inhibition of autophagy impacts PDA growth through reprogrammed tumor and
stromal cell function. The potential of ULK inhibitors in rescuing autophagy-dependent therapeutic resistance to
chemotherapies, MEK inhibitors, and immune checkpoint inhibition will be explored.
项目总结-项目3:自噬
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Reuben Shaw其他文献
Reuben Shaw的其他文献
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{{ truncateString('Reuben Shaw', 18)}}的其他基金
Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer
解码并靶向癌症中的 LKB1-AMPK 信号通路
- 批准号:
10667573 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer
解码并靶向癌症中的 LKB1-AMPK 信号通路
- 批准号:
10448279 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer
解码并靶向癌症中的 LKB1-AMPK 信号通路
- 批准号:
10222594 - 财政年份:2017
- 资助金额:
$ 46.68万 - 项目类别:
AMPK and AMPK-related kinases in lung cancer development and treatment
AMPK 和 AMPK 相关激酶在肺癌发生和治疗中的作用
- 批准号:
8605862 - 财政年份:2013
- 资助金额:
$ 46.68万 - 项目类别:
AMPK and AMPK-related kinases in lung cancer development and treatment
AMPK 和 AMPK 相关激酶在肺癌发生和治疗中的作用
- 批准号:
8785659 - 财政年份:2013
- 资助金额:
$ 46.68万 - 项目类别:
AMPK and AMPK-related kinases in lung cancer development and treatment
AMPK 和 AMPK 相关激酶在肺癌发生和治疗中的作用
- 批准号:
8420203 - 财政年份:2013
- 资助金额:
$ 46.68万 - 项目类别:
AMPK and AMPK-related kinases in lung cancer development and treatment
AMPK 和 AMPK 相关激酶在肺癌发生和治疗中的作用
- 批准号:
9186506 - 财政年份:2013
- 资助金额:
$ 46.68万 - 项目类别:
AMPK and AMPK-related kinases in lung cancer development and treatment
AMPK 和 AMPK 相关激酶在肺癌发生和治疗中的作用
- 批准号:
8984294 - 财政年份:2013
- 资助金额:
$ 46.68万 - 项目类别:
Role of LKB1 and AMPK in Metformin and TZD Control of Glucose Metabolism in Liver
LKB1 和 AMPK 在二甲双胍和 TZD 控制肝脏葡萄糖代谢中的作用
- 批准号:
7353028 - 财政年份:2007
- 资助金额:
$ 46.68万 - 项目类别:
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