Targeting MLL/Menin in AML
AML 中的目标 MLL/Menin
基本信息
- 批准号:10220875
- 负责人:
- 金额:$ 2.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-19 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaApoptosisAzacitidineBiologicalBiological MarkersBiological ModelsBiotechnologyBromodomainCell Differentiation processCell ProliferationCellsChromatinChromosome StructuresClinicalClinical ResearchClinical assessmentsComplexDevelopmentDoctor of MedicineDoctor of PhilosophyEZH2 geneEnzyme ActivationFLT3 geneFLT3 inhibitionFLT3 inhibitorFoundationsFutureGene ExpressionGene RearrangementGenesGeneticHOXA9 geneHematopoieticHistonesHomeobox GenesIn VitroKDM1A geneLeadLeukemic CellMEIS1 geneMLL geneMLL-rearranged leukemiaMaintenanceMeninModelingMultiprotein ComplexesMutationMyeloproliferative diseaseNPM1 genePatientsPharmaceutical PreparationsPhase I Clinical TrialsProcessProteinsReceptor Protein-Tyrosine KinasesRefractoryRelapseResistanceTherapeuticTimeTranslatingWorkacute myeloid leukemia cellbasecell growthearly phase clinical trialearly phase trialexperimental studyfunctional genomicsin vivoinhibitor/antagonistleukemialeukemia relapsemouse modelmutantpatient derived xenograft modelphase I trialpreclinical studyprogramsprotein complexresistance mechanismresponsesmall moleculesmall molecule inhibitortranscription factortreatment strategy
项目摘要
Abstract:
Inappropriate expression of genes such as the homeotic (HOX) genes is found in up to 40% of cases of Acute
Myelogenous Leukemia (AML). Two well-known genetic subsets, those with MLL-rearrangements and those
with NPM1 mutations, are known to possess high-level expression of HOX genes and have been shown to be
dependent on continued expression of these genes. Recent studies have defined the protein complexes that
maintain this aberrant gene expression. Furthermore, multiple groups and pharma/biotech companies have now
developed small molecule inhibitors of these complexes. Some of these small molecules, particularly those
targeting DOT1L, EZH2 and Bromodomains) have recently entered early phase trials and have shown interesting
biological and some complete clinical responses. Another approach to target chromatin associated complexes
is inhibition of the MLL1-Menin interaction, an approach that has also been shown to reverse HOX gene
expression. In this proposal we will characterize newly developed MLL1-Menin inhibitors and work to bring one
of these small molecules to clinical assessment. In Specific Aim 1 we will characterize the effects on gene
expression and chromatin state after inhibition of the MLL1-Menin interaction in MLL-rearranged and NPM1
mutant AML cells. In Specific Aim 2 we will assess the combination of MLL1-Menin inhibitors with either
azacitidine, DOT1L inhibitors or FLT3 inhibitors. In Specific Aim 3 we will initiate a phase 1 trial of MLL-1 Menin
inhibitors alone and in combination with a azacitidine. These trials that will set the foundation for further
assessment of combinations based on results from preclinical studies described here. The proposed
experiments will propel MLL1-Menin inhibitors to clinical assessment and importantly define combination
approaches that should be assessed in future clinical studies.
摘要:
在高达40%的急性胰腺炎病例中发现了基因如同源异型(HOX)基因的不适当表达。
骨髓性白血病(AML)。两个众所周知的遗传子集,那些与ML重排和那些
具有NPM 1突变的人,已知具有HOX基因的高水平表达,并且已被证明是
依赖于这些基因的持续表达。最近的研究已经确定了蛋白质复合物,
维持这种异常的基因表达。此外,多个集团和制药/生物技术公司现在已经
开发了这些复合物的小分子抑制剂。其中一些小分子,特别是那些
靶向DOT 1 L、EZH 2和Bromodomains)最近进入早期试验,
生物学和一些完整的临床反应。靶向染色质相关复合物的另一种方法
抑制MLL 1-Menin相互作用,这种方法也被证明可以逆转HOX基因,
表情在这项提案中,我们将表征新开发的MLL 1-Menin抑制剂,并努力使之
这些小分子的临床评估。在具体目标1中,我们将描述对基因的影响。
MLL重排和NPM 1中MLL 1-Menin相互作用抑制后的表达和染色质状态
突变AML细胞。在具体目标2中,我们将评估MLL 1-Menin抑制剂与以下任一种的组合:
阿扎胞苷、DOT 1 L抑制剂或FLT 3抑制剂。在具体目标3中,我们将启动MLL-1 Menin的1期试验
单独的抑制剂和与阿扎胞苷的组合。这些试验将为未来的
基于本文所述临床前研究的结果评估组合。拟议
实验将推动MLL 1-Menin抑制剂进入临床评估,并重要地定义组合
这些方法应在未来的临床研究中进行评估。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SCOTT A ARMSTRONG其他文献
SCOTT A ARMSTRONG的其他文献
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{{ truncateString('SCOTT A ARMSTRONG', 18)}}的其他基金
The Center for Therapeutic Targeting of EWS-oncoproteins
EWS癌蛋白治疗靶向中心
- 批准号:
10671815 - 财政年份:2022
- 资助金额:
$ 2.05万 - 项目类别:
The Center for Therapeutic Targeting of EWS-oncoproteins
EWS癌蛋白治疗靶向中心
- 批准号:
10382013 - 财政年份:2021
- 资助金额:
$ 2.05万 - 项目类别:
Defining epigenetic mechanisms in NPM1c mutant leukemia
定义 NPM1c 突变白血病的表观遗传机制
- 批准号:
10184546 - 财政年份:2021
- 资助金额:
$ 2.05万 - 项目类别:
Defining epigenetic mechanisms in NPM1c mutant leukemia
定义 NPM1c 突变白血病的表观遗传机制
- 批准号:
10640846 - 财政年份:2021
- 资助金额:
$ 2.05万 - 项目类别:
Defining epigenetic mechanisms in NPM1c mutant leukemia
定义 NPM1c 突变白血病的表观遗传机制
- 批准号:
10388249 - 财政年份:2021
- 资助金额:
$ 2.05万 - 项目类别:
Targeting DOT1L for Degradation in MLL-rearranged Leukemia
靶向 DOT1L 降解 MLL 重排白血病
- 批准号:
10411945 - 财政年份:2012
- 资助金额:
$ 2.05万 - 项目类别:
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