Acute myeloid leukemia (AML) Research Project

急性髓系白血病（AML）研究项目

• 批准号: 10733236
• 负责人: MARTIN CARROLL
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733236
• 关键词: Acute Myelocytic Leukemia; Address; Biology; Chimeric Proteins; Classification; Clinical; Collection; Combined Modality Therapy; Communities; Complex; DNMT3a; Data; Development; Disease; Documentation; Drug Combinations; Engraftment; Epigenetic Process; FLT3 gene; FLT3 inhibitor; Failure; Genetic; Human; MLL gene; Malignant Neoplasms; Menin; Mixed-Lineage Leukemia; Modeling; Molecular; Mouse Strains; Mus; Mutate; Mutation; Oncogenes; Pathogenesis; Pennsylvania; Performance; Pharmaceutical Preparations; Phase; Phenotype; Pre-Clinical Model; Proteins; Relapse; Research Project Grants; Sampling; Subgroup; Survival Rate; TP53 gene; Therapeutic; Tissue Transplantation; Transplant-Related Disorder; Transplantation; United States National Institutes of Health; Universities; Xenograft procedure; advanced disease; cohort; disorder subtype; drug development; drug testing; in vivo; inhibitor; leukemia; leukemic stem cell; molecular modeling; molecular targeted therapies; mutant; new therapeutic target; next generation sequencing; novel; novel therapeutics; nucleophosmin; patient derived xenograft model; phase II trial; response; targeted treatment; therapy development; transcriptome sequencing; treatment response

Summary Acute myeloid leukemia (AML) is one of the most intensely studied of human malignancies. In recent years there have been major advances in defining the molecular pathogenesis of AML and introduction of new therapies. But the three-year survival rate remains below 50% indicating failures to make therapeutic advances for the disease. In part, we believe that this reflects a failure to adequately use genetically defined PDX models to develop new therapies targeted at molecularly defined subsets of the disease. As discussed below, although the overall genetics of AML is complex, we and others have found that there are dominant oncogenes in AML and that targeting of these oncogenes can induce therapeutic responses although not cures. Examples of this approach include the use of FLT3 inhibitors for de novo and relapsed FLT3 ITD mutant AML and development of IDH1 and IDH2 inhibitors. In each of these cases, current therapy includes a choice of targeted therapies which are active but not curative. This likely reflects the multi-variate molecular pathogenesis. To advance the field, we have collected thousands of independent AML collections and characterized dozens of PDX models of AML. These models have been widely used for studies of basic biology but here we propose to advance the use of AML PDX modeling for therapy development. There are several obstacles to progress. First, there are not widely available and well characterized AML PDX models defined by genetic alterations. To address this concern, we have chosen to separate AML into 7 subsets defined by dominant oncogenes as recently done by the NIH MyeloMatch study. Leukemia’s will be sub-classified based on mutations in FLT3, DNMT3A, NPM1c, IDH1, IDH2, TP53 or KMT2A fusion protein (FP). Here we will characterize xenotransplantation of three AML models for each of these seven sub-groups and specifically characterize the biology of serial transplant of AML in the NSG mouse strain. Initial documentation of engraftment has already been completed for 33 of the 35 samples. In SA2, we will focus on performance of an XP2 study to direct ongoing clinical efforts. Two of these sub-groups are defined by the presence of fusion proteins involving KMT2A (previously mixed lineage leukemia or MLL) or Nucleophosmin (NPM) mutations (that cause cytosolic re-localization of the protein) (NPMc). Both of these sub-types of AML require menin, an epigenetic co-regulator for pathogenesis and AML’s with either class of mutations responding in pre-clinical models to Menin inhibition. Menin inhibitors are currently in Phase 1 and Phase 2 human studies and early results suggest that these drugs, like other targeted therapies in AML, are active but not curative. Recent results have suggested that enhanced differentiation of AML samples containing KMT2A fusion proteins (FP) can be achieved by combining a Menin inhibitor with a KAT6A inhibitor. Here we will use our characterized KMT2A FP and NPMc mutant AML PDX models to study the effect in vivo of targeting both proteins in genetically defined subsets of AML.

概括 急性髓样白血病（AML）是人类恶性肿瘤中最积极的研究之一。最近几年 在定义AML的分子发病机理和引入新的方面取得了重大进展 疗法。但是三年的生存率仍低于50％，表明失败以取得热量进步 为了疾病。在某种程度上，我们认为这反映了未能充分使用一般定义的PDX模型 开发针对分子定义的疾病子集的新疗法。如下所述，尽管 AML的整体遗传学很复杂，我们和其他人发现AML中存在主导性癌基因 这些癌症基因的靶向可以诱导热反应，尽管无法治愈。这个例子 方法包括将FLT3抑制剂用于从头和中继FLT3 ITD突变体AML和开发 IDH1和IDH2抑制剂。在每种情况下，当前的疗法都包括选择目标疗法 活跃但不能治愈。这可能反映了多变量的分子发病机理。推进 领域，我们收集了数千种独立的AML收集，并表征了数十个PDX模型 AML。这些模型已被广泛用于基本生物学研究，但在这里我们建议 将AML PDX建模用于治疗开发。有几个障碍可以进步。首先，有 不是广泛的可用且特征良好的AML PDX模型，这些模型由遗传改变定义。解决这个问题 令人担忧的是，我们选择将AML分离为7个由主要的肿瘤基因定义的子集， NIH骨髓匹配研究。白血病将根据FLT3，DNMT3A，NPM1C的突变进行亚分类。 IDH1，IDH2，TP53或KMT2A融合蛋白（FP）。在这里，我们将表征三个AML的异种移植 这七个子组中的每一个的模型，并专门表征了AML系列移植的生物学 在NSG小鼠菌株中。植入的初始文档已经完成了33个中的33个 样品。在SA2中，我们将专注于XP2研究的性能，以指导正在进行的临床工作。其中两个 亚组由涉及KMT2A的融合蛋白（以前混合谱系白血病）定义 或MLL）或核素（NPM）突变（引起蛋白质的胞质重新定位）（NPMC）。两个 这些AML的子类型需要Menin，Menin是一种发病机理的表观遗传学共同调节剂，而AML与任何一类 在临床前模型中对Menin抑制作用响应的突变。梅宁抑制剂目前处于第1阶段， 第2阶段的人类研究和早期结果表明，与AML中的其他靶向疗法一样，这些药物也是 活跃但无法治愈。最近的结果表明，增强了包含AML样品的分化 可以通过将MENIN抑制剂与Kat6a抑制剂组合来实现KMT2A融合蛋白（FP）。我们在这里 将使用我们特征的KMT2A FP和NPMC突变体AML PDX模型来研究靶向的效果 两种蛋白在AML的一般定义子集中。