Pathologic Signaling Pathways in AML Cells
AML 细胞中的病理信号通路
基本信息
- 批准号:10553601
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAffectAmericanBindingBiochemical PathwayBiological AssayCell CountCell Cycle RegulationCell LineCell ProliferationCell SurvivalClinicalClinical TrialsComplexCytarabineDNADataDiseaseDrug CombinationsEngraftmentEquilibriumEtoposideFLT3 geneFLT3 inhibitorFOXO3A geneFRAP1 geneGenerationsGrowth FactorHematopoietic NeoplasmsHumanIL3 GeneIn VitroIndividualInositolLaboratoriesLeadLeukemic CellLifeMetabolicMethodologyMethodsModelingMusMutatePIK3CG genePathogenesisPathologicPathway interactionsPatient-Focused OutcomesPatientsPharmaceutical PreparationsPhosphorylationPhosphotransferasesPre-Clinical ModelProcessProteinsProto-Oncogene Proteins c-aktRegulationRelapseReportingResearch DesignResearch ProposalsSamplingSeriesSignal PathwaySignal TransductionSirolimusTherapeuticTranscriptional RegulationTranslationsUnited StatesUnited States National Institutes of HealthVeteransWorkXenograft Modelacute myeloid leukemia cellc-myc Genescancer cellcell growthcell transformationchemotherapychromatin immunoprecipitationcombinatorialcytotoxicimprovedin vivoinhibitorinsulin signalingleukemic stem cellmolecular subtypesnovel strategiesnovel therapeuticspromotersmall molecule inhibitorsuccess
项目摘要
Abstract: Acute myeloid leukemia (AML) is a serious blood cancer that affects United
States Veterans and other individuals. Multiple studies have demonstrated that active
signaling pathways are a necessary step to leukemic cell transformation. However, the
mechanism(s) of activated signaling in FLT3 wild type AML are poorly described. We
hypothesize that constitutive activation of the PI3 kinase pathway leads to activation of a
complex called mammalian target of rapamycin 2 (mTORC2) which regulates diverse
pathways to balance cell growth and survival in AML cells. In this proposal, we will
define these signaling pathways and determine if inhibition of mTORC2 alone or in
combination with other drugs will enhance survival in pre-clinical models of AML
leading to new therapies for this challenging disease.
1. Objective(s): The overall objective of the research proposal is to define the
mechanisms of activated cell signaling in AML cells, determine the biochemical
pathways regulated by mTORC2 in AML cells and determine if inhibition of mTORC2
in pre-clinical models can increase survival of individuals with AML.
2. Research Design: We propose three Specific Aims. Specific Aim 1) Confirm that
4EBP1 is a target of MTORC2 and not MTORC1 in human AML samples and define
whether MTORC2 regulates cell survival or cell growth. Specific Aim 2) Determine if
mTORC2 Regulates FOXO 3 phosphorylation in AML cells to Regulate Cell Survival.
Specific Aim 3) Determine if combinatorial MTORC1/MTORC2 inhibition in
combination with chemotherapy or Bcl2 inhibition suppresses AML cell growth in pre-
clinical models.
3. Methodology: Specific Aim 1 will primary use human AML cells and primary
human AML cells in culture. Specific Aim 2 will use similar methods but also assess
FOXO binding to DNA using chromatin immunoprecipitation. Specific Aim 3 will focus
on studies in a xenotransplantation model of AML developed by our laboratory.
4. Findings: We anticipate confirming that mTORC2 is actually a master regulator of
signaling in AML cells. In particular, we anticipate that mTORC2 regulates 4EBP1 to
regulate protein translation. We also anticipate that mTORC2 regulates FOXO proteins to
regulate c-Myc expression. Finally, we anticipate that mTORC2 inhibition will work
alone or in combination with other therapies to inhibit AML cell survival in vivo.
5. Clinical Relationships: These studies will use primary material from patients with
AML and will be used to develop a new approach to therapy of the disease.
摘要:急性髓系白血病(Acute myeloid leukemia, AML)是一种严重影响人类健康的血癌
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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MARTIN CARROLL其他文献
MARTIN CARROLL的其他文献
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{{ truncateString('MARTIN CARROLL', 18)}}的其他基金
University of Pennsylvania Patient-derived Xenograft Development and Trials Center
宾夕法尼亚大学患者来源的异种移植开发和试验中心
- 批准号:
10733231 - 财政年份:2023
- 资助金额:
-- - 项目类别:
University of Pennsylvania Patient-derived Xenograft Development and Trials Center
宾夕法尼亚大学患者来源的异种移植开发和试验中心
- 批准号:
10733232 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
- 批准号:
9114538 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
- 批准号:
9295847 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
- 批准号:
8946188 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
- 批准号:
9512555 - 财政年份:2015
- 资助金额:
-- - 项目类别:
(PDQ5)Integrated Genetic and Epigenetic Prognostication for Acute Myeloid Leukemi
(PDQ5)急性髓性白血病的综合遗传和表观遗传预测
- 批准号:
8687082 - 财政年份:2014
- 资助金额:
-- - 项目类别:
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