Targeting MLL/Menin in AML

AML 中的目标 MLL/Menin

基本信息

批准号：
10220875
负责人：
SCOTT A ARMSTRONG
金额：
$ 2.05万
依托单位：
DANA-FARBER CANCER INST
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：
https://reporter.nih.gov/project-details/10220875
关键词：
Acute Myelocytic Leukemia Apoptosis Azacitidine Biological Biological Markers Biological Models Biotechnology Bromodomain Cell Differentiation process Cell Proliferation Cells Chromatin Chromosome Structures Clinical Clinical Research Clinical assessments Complex Development Doctor of Medicine Doctor of Philosophy EZH2 gene Enzyme Activation FLT3 gene FLT3 inhibition FLT3 inhibitor Foundations Future Gene Expression Gene Rearrangement Genes Genetic HOXA9 gene Hematopoietic Histones Homeobox Genes In Vitro KDM1A gene Lead Leukemic Cell MEIS1 gene MLL gene MLL-rearranged leukemia Maintenance Menin Modeling Multiprotein Complexes Mutation Myeloproliferative disease NPM1 gene Patients Pharmaceutical Preparations Phase I Clinical Trials Process Proteins Receptor Protein-Tyrosine Kinases Refractory Relapse Resistance Therapeutic Time Translating Work acute myeloid leukemia cell base cell growth early phase clinical trial early phase trial experimental study functional genomics in vivo inhibitor/antagonist leukemia leukemia relapse mouse model mutant patient derived xenograft model phase I trial preclinical study programs protein complex resistance mechanism response small molecule small molecule inhibitor transcription factor treatment 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.

抽象的：在高达 40% 的急性病例中发现了基因的不适当表达，例如同源异型 (HOX) 基因骨髓性白血病（AML）。两个众所周知的遗传子集，即具有 MLL 重排的遗传子集和具有 MLL 重排的遗传子集具有 NPM1 突变，已知具有 HOX 基因的高水平表达，并且已被证明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 DOT1L、EZH2 和 Bromodomains）最近进入了早期试验并显示出有趣的结果生物学反应和一些完整的临床反应。另一种靶向染色质相关复合物的方法抑制 MLL1-Menin 相互作用，这种方法也被证明可以逆转 HOX 基因表达。在本提案中，我们将描述新开发的 MLL1-Menin 抑制剂的特征，并努力将一种对这些小分子进行临床评估。在具体目标 1 中，我们将描述对基因的影响抑制 MLL1-Menin 相互作用后 MLL 重排和 NPM1 的表达和染色质状态突变的 AML 细胞。在具体目标 2 中，我们将评估 MLL1-Menin 抑制剂与以下任一药物的组合：阿扎胞苷、DOT1L 抑制剂或 FLT3 抑制剂。在具体目标 3 中，我们将启动 MLL-1 Menin 的 1 期试验单独使用抑制剂或与阿扎胞苷组合使用抑制剂。这些试验将为进一步的研究奠定基础根据此处描述的临床前研究结果对组合进行评估。拟议的实验将推动 MLL1-Menin 抑制剂进行临床评估，并重要的是确定组合应在未来的临床研究中评估的方法。