Targeting DOT1L for Degradation in MLL-rearranged Leukemia
Targeting DOT1L for Degradation in MLL-rearranged Leukemia
批准号:
10411945
负责人:
SCOTT A ARMSTRONG
金额:
$39.6万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-25 至 2023-05-31
关键词:
Acute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAcute leukemiaAddressAdultApoptoticAreaAutomobile DrivingBindingBiologicalBiological AssayBiological ModelsBiologyCell Culture TechniquesCell LineCell modelCellsChemicalsChemistryChildChildhoodChildhood LeukemiaChimeric ProteinsChromatin StructureChromosomal translocationClinicClinicalClinical TrialsCommunitiesContinuous Intravenous InfusionCoupledDependenceDevelopmentDiagnosisDiseaseDoseDrug DesignDrug resistanceEffectivenessEnzymesEpigenetic ProcessFoundationsFundingGene ExpressionGenerationsGenesGeneticGenetic studyGrantHematopoiesisHematopoieticHematopoietic Stem Cell TransplantationHistonesHomeoboxHumanHypermethylationIn VitroJointsKnowledgeLaboratoriesLeadLeukemic CellLinkLysineMLL geneMLL-AF9MLL-rearranged leukemiaMaintenanceMalignant NeoplasmsMedicalMethylationMethyltransferaseModelingMusNPM1 geneOncogenicOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhase I Clinical TrialsPlayPrognosisProtein EngineeringProteinsPublicationsQiReagentRefractoryRelapseReportingResearchResistanceResistance developmentRoleSignal TransductionSystemTestingTherapeuticTherapeutic TrialsTranslationsWorkacute myeloid leukemia cellbasechemical geneticschemotherapychromatin modificationclinical candidateclinical investigationcombinatorialdrug actiondrug discoveryepigenomicsexperiencegene translocationgenetic approachgenome-widehistone methyltransferasehuman modelin vivoinhibitorinhibitor therapyinsightlead optimizationleukemialeukemogenesismembermutantnovelnovel therapeuticspatient derived xenograft modelpre-clinicalpreclinical studypreventprogramsprotein degradationprotein functionrecruitresistance mechanismresponsescaffoldsmall moleculesmall molecule inhibitorstem cellssuccesstargeted treatmenttooltranslational modeltumor progressionubiquitin-protein ligase
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Despite marked progress in the rate of cure among patients with acute leukemia, chromosomal translocations
involving the mixed lineage leukemia gene (MLL1) give rise to highly aggressive acute leukemias associated
with poor clinical outcomes for pediatric and adult patients. Current treatment options are of limited effectiveness;
thus, there is a pressing need for new therapies for this disease. Genetic studies have demonstrated that the
histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged (MLL-r)
leukemia in model systems. Likewise, work from the previous funding cycle clearly defined a role for DOT1L
inhibition in MLL-r leukemia through characterization of a potent, specific DOT1L inhibitor, EPZ-5676
(pinometostat), that has remarkably selective anti-proliferative and pro-apoptotic effects on MLL-rearranged
cells. As pinometostat has progressed through Phase I clinical trials, responses and subsequent relapses imply
the development of acquired resistance to the inhibitor. In this proposal, we seek to understand the biological
underpinnings of DOT1L inhibitor resistance and develop a novel class of small molecule DOT1L degraders to
overcome resistance. In Specific Aim 1, we seek to understand the mechanisms of resistance through detailed
studies of chromatin structure and gene expression following the development of acquired resistance to DOT1L
inhibitor therapy. We will also investigate the non-enzymatic role of DOT1L in MLL-r leukemia and define
dependencies acquired in the resistant state. In Specific Aim 2, we will lead a chemistry and chemical biology
campaign and develop an assay platform for the identification and optimization of the first small molecule
degraders of endogenous DOT1L protein. In Specific Aim 3, we will utilize our cell culture and patient-derived
xenograft models of MLL-r leukemia to explore the impact of DOT1L degradation on gene expression and tumor
progression while driving hit-to-lead optimization of DOT1L degraders that can prompt clinical investigation. We
will also test pharmacological hypotheses regarding combinatorial drug action with DOT1L degraders in
predictive human models of MLL-r leukemia. We expect these aims to bring new more efficacious, less toxic
therapies to children and adults diagnosed with this devastating disease.
期刊论文(11)
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DOI:
10.1002/9780470559277.ch150024
发表时间:
2015-12-02
期刊:
Current protocols in chemical biology
影响因子:
--
作者:
[Roberts JM, Bradner JE]
通讯作者:
Bradner JE
DOI:
10.1016/j.ccell.2014.10.009
发表时间:
2014-12-08
期刊:
Cancer cell
影响因子:
50.3
作者:
[Deshpande AJ, Deshpande A, Sinha AU, Chen L, Chang J, Cihan A, Fazio M, Chen CW, Zhu N, Koche R, Dzhekieva L, Ibáñez G, Dias S, Banka D, Krivtsov A, Luo M, Roeder RG, Bradner JE, Bernt KM, Armstrong SA]
通讯作者:
Armstrong SA
DOI:
10.1038/nature21688
发表时间:
2017-03-09
期刊:
Nature
影响因子:
64.8
作者:
[Erb MA, Scott TG, Li BE, Xie H, Paulk J, Seo HS, Souza A, Roberts JM, Dastjerdi S, Buckley DL, Sanjana NE, Shalem O, Nabet B, Zeid R, Offei-Addo NK, Dhe-Paganon S, Zhang F, Orkin SH, Winter GE, Bradner JE]
通讯作者:
Bradner JE
Genomic dark matter sheds light on EVI1-driven leukemia.
基因组暗物质揭示了 EVI1 驱动的白血病。
DOI:
10.1016/j.ccr.2014.03.031
发表时间:
2014
期刊:
Cancer cell
影响因子:
50.3
作者:
[Koche,RichardP, Armstrong,ScottA]
通讯作者:
Armstrong,ScottA
DOI:
10.1016/j.molcel.2017.06.004
发表时间:
2017-07-06
期刊:
Molecular cell
影响因子:
16
作者:
[Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ, Roberts JM, Zeid R, Scott TG, Paulk J, Lachance K, Olson CM, Dastjerdi S, Bauer S, Lin CY, Gray NS, Kelliher MA, Churchman LS, Bradner JE]
通讯作者:
Bradner JE
共 8 条
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Defining epigenetic mechanisms in NPM1c mutant leukemia
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Targeting to Epigenetic Modications in ALL
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资助金额:$40.23万
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Targeting to Epigenetic Modications in ALL
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资助金额:$40.23万
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MLL FUSION GENES IN MYELOID AND LYMPHOID LEUKEMIAS
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Molecular pathogenesis of MLL-AF4 leukemias
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Molecular pathogenesis of MLL-AF4 leukemias
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Molecular pathogenesis of MLL-AF4 leukemias
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Molecular pathogenesis of MLL-AF4 leukemias
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Research Training in Pediatric Oncology
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海外基金