STAT3 inhibition as a therapeutic strategy against MDS stem cells

STAT3 抑制作为针对 MDS 干细胞的治疗策略

基本信息

批准号：
10206262
负责人：
Ulrich Steidl
金额：
$ 53.2万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206262
关键词：
Acute Myelocytic Leukemia Apoptotic Azacitidine Biological Biological Assay Cell Line Cells ChIP-seq Clinical Data Development Disease Disease Progression Disease remission Dysmyelopoietic Syndromes Dysplasia Enhancers Evaluable Disease Future Genetic Genomics Growth Hematological Disease Hematopoietic Neoplasms Hematopoietic stem cells Human In Vitro MCL1 gene Marrow Medicine Modeling Molecular Morphology Mutation NUP98 gene Nature Outcome Pathogenesis Pathway interactions Patients Phenotype Population Prognosis Recurrent disease Relapse Role STAT3 gene Sampling Solid Neoplasm Source Testing Therapeutic Xenograft procedure cancer stem cell chemotherapy clinical application clinical efficacy clinically relevant cohort conventional therapy curative treatments efficacy testing epigenomics granulocyte-monocyte progenitors improved in vivo in vivo Model inhibitor/antagonist leukemia leukemic transformation mouse model novel overexpression prevent progenitor relapse prediction response self-renewal stem stem cell growth stem cells therapeutic target transcription factor transcriptomics

项目摘要

Myelodysplastic syndromes (MDS) are generally incurable hematologic disorders associated with disease initiating stem cells that are not eliminated by conventional therapies and need to be targeted for potentially curative strategies. We recently demonstrated that aberrant hematopoietic stem cells are expanded in MDS, can persist during phenotypic remissions and can predict relapse. STAT3 is a transcription factor that was found to be overexpressed in MDS stem cells and higher expression was associated with an adverse prognosis in a large cohort of patients. We also obtained proof-of-concept data that inhibition of STAT3 can target malignant stem cells while sparing healthy control stem and progenitors, thus identifying it as a potential therapeutic target in MDS. To comprehensively examine the role of this pathway in MDS, Aim 1 will define the functional role of STAT3 on growth of disease initiating stem cells in MDS and determine the efficacy of clinically relevant inhibitors of this pathway in large cohort of primary human samples. Additionally, in vitro and in vivo efficacy of a clinically applicable, anti-sense inhibitor (AZD-9150) against a large number of primary MDS samples will be correlated with clinical and mutational subtypes to identify subsets that will be sensitive to STAT3 inhibition. Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will determine the requirement for STAT3 in initiation of dysplasia/disease progression in vivo by genetic deletion of STAT3 in two mouse models of MDS. Along with the NUP-HOXD13 model; a novel model of MDS dysplasia and transformation which we have recently developed, induced by heterozygous PU.1 enhancer deletion, will be used to study the effect of STAT3 deletion on disease initiating stem cells and disease progression. Aim 3 will identify the downstream effectors of STAT3 activation in MDS. Combination of Chip-seq and transcriptomic profiling will be used to identify direct targets of STAT3 activation, that will tested in functional assays in MDS models. We will also determine the role of MCL-1 as a downstream anti-apoptotic target of STAT3 activation in MDS stem cells. Identification of critical downstream effectors will improve our molecular understanding of the STAT3 pathway in MDS and will be instrumental to develop more specific and potent strategies to inhibit this pathway. Taken together, these studies will study the role of the STAT3 pathway in MDS pathogenesis and determine its potential as a therapeutic target against immature, disease initiating cells in MDS.

骨髓增生异常综合征 (MDS) 通常是无法治愈的血液系统疾病疾病引发的干细胞无法通过常规疗法消除，需要成为潜在治疗策略的目标。我们最近证明了异常造血干细胞在 MDS 中扩增，可以在表型缓解期间持续存在，并且可以预测复发。 STAT3 是一种转录因子，被发现在 MDS 中过度表达在一大群人中，干细胞和较高的表达与不良预后相关患者。我们还获得了概念验证数据，表明抑制 STAT3 可以靶向恶性细胞干细胞，同时保留健康的对照干细胞和祖细胞，从而将其确定为潜在的 MDS 的治疗目标。为了全面检查该通路在 MDS 中的作用，目标 1 将定义 STAT3 对 MDS 中疾病起始干细胞生长的功能作用，确定该途径的临床相关抑制剂在大型原发性队列中的功效人类样本。此外，临床上适用的反义药物的体外和体内功效针对大量原发性 MDS 样本的抑制剂（AZD-9150）将与临床和突变亚型，以确定对 STAT3 抑制敏感的子集。患者来源的 MDS 异种移植物也将用于确定体内疗效。目标2将通过以下方式确定 STAT3 在体内发育不良/疾病进展起始中的需求两种 MDS 小鼠模型中 STAT3 基因缺失。与 NUP-HOXD13 型号一起；一个我们最近开发的MDS不典型增生和转化的新模型，诱导通过杂合 PU.1 增强子缺失，将用于研究 STAT3 缺失对疾病引发干细胞和疾病进展。目标 3 将确定下游 MDS 中 STAT3 激活的效应子。 Chip-seq 和转录组分析的结合将用于识别 STAT3 激活的直接靶标，该靶标将在功能测定中进行测试 MDS 模型。我们还将确定 MCL-1 作为下游抗凋亡靶点的作用 MDS 干细胞中的 STAT3 激活。关键下游效应器的识别将得到改善我们对 MDS 中 STAT3 通路的分子理解将有助于开发抑制该途径的更具体和有效的策略。总的来说，这些研究将研究 STAT3 通路在 MDS 发病机制中的作用并确定其作为治疗药物的潜力针对 MDS 中未成熟的疾病起始细胞的治疗靶点。