Therapeutic targeting of MDS stem cells

MDS 干细胞的治疗靶向

基本信息

批准号：
9767250
负责人：
Ulrich Steidl
金额：
$ 52.89万
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：
2018
资助国家：
美国
起止时间：
2018-08-20 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767250
关键词：
Antibodies Automobile Driving Azacitidine Biological CD34 gene Cell Fraction Cell Line Cells Clinical Data Dependence Disease Disease Progression Disease remission Dysmyelopoietic Syndromes Dysplasia Enhancers Genetic Genetic Transcription Growth Hematological Disease Hematopoietic Neoplasms Hematopoietic stem cells Human IL8 gene IL8RB gene IRAK1 gene Immune Immune signaling Interleukin 7 Receptor Interleukin 8A Receptor Interleukin Activation Interleukin-8 Interleukin-8B Receptor Marrow Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mutation NUP98 gene Outcome Pathogenesis Pathway interactions Patients Pharmacology Phenotype Population Prognostic Factor Recurrent disease Relapse Role Sampling Signal Pathway Stem cells Testing Transfusion Xenograft procedure cell growth chemotherapy clinical application clinical efficacy clinically relevant cohort conventional therapy efficacy testing humanized antibody improved in vivo in vivo Model inhibitor/antagonist knock-down leukemia leukemic transformation mouse model new therapeutic target novel outcome forecast overexpression prevent progenitor relapse prediction response self-renewal small hairpin RNA small molecule stem therapeutic target

项目摘要

MDS is a generally incurable hematologic disorder 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. In preliminary studies, we demonstrate that Interleukin 8 (IL8) is consistently and selectively overexpressed in stem cells from MDS patients. The receptor for IL8, CXCR2, is also significantly increased in large MDS patient cohorts and is associated with a worse prognosis. Functionally, IL8/CXCR2 pathway inhibition by either shRNA-mediated knockdown or pharmacologic approaches abrogated proliferation in cell lines and primary MDS samples. Importantly, inhibition of the IL8/CXCR2 pathway selectively inhibited immature stem cells from MDS samples without an effect on healthy HSCs, and also had demonstrated efficacy in xenografts. To comprehensively examine the role of this pathway in MDS, Aim 1 will define the functional role of IL-8/CXCR2 pathway 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, responses to IL8/CXCR2 inhibition with small molecules and a novel humanized antibody will be correlated with clinical and mutational subtypes to identify targetable subsets that will be sensitive to IL8/CXCR2 inhibition. Patient derived MDS xenografts will also be used to determine in vivo efficacy. Aim 2 will determine the requirement for CXCR2 in initiation of dysplasia/disease progression in vivo by genetic deletion of CXCR2 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 CXCR2 deletion on disease initiating stem cells and disease progression. Aim 3 will identify the mechanisms of activation of the IL8-CXCR2 pathway and determine its downstream effectors in MDS. IL8 is a known component of innate immune signaling cascades, and we will determine whether upstream immune activators, IL1RAP, TLRs and IRAK1/4 are driving overactivation of the IL8/CXCR2 pathway in MDS. We will also evaluate the activation and functional significance of PI3Kinase and MAP kinase pathways as downstream effectors of the IL8/CXCR2 pathway in MDS. Taken together, these studies will study the role of the IL8/CXCR2 pathway in MDS pathogenesis and determine its potential as a therapeutic target against immature, disease initiating cells in MDS.

MDS 是一种与疾病引发干细胞相关的通常无法治愈的血液疾病传统疗法无法消除，需要针对潜在的治愈方法策略。我们最近证明，异常的造血干细胞在 MDS 可以在表型缓解期间持续存在，并且可以预测复发。在初步研究中，我们证明白细胞介素 8 (IL8) 在干细胞中持续且选择性地过表达来自 MDS 患者。 IL8 受体 CXCR2 在大型 MDS 中也显着增加患者群体，并与较差的预后相关。从功能上讲，IL8/CXCR2 通路 shRNA 介导的基因敲除或药理学方法的抑制被消除细胞系和原代 MDS 样品中的增殖。重要的是，抑制 IL8/CXCR2 途径选择性抑制 MDS 样本中的未成熟干细胞，而不影响健康 HSCs 也已在异种移植中显示出功效。全面审视角色为了了解该通路在 MDS 中的作用，目标 1 将定义 IL-8/CXCR2 通路对 MDS 生长的功能作用 MDS 中的疾病起始干细胞，并确定临床相关抑制剂的功效这一途径存在于大量原始人类样本中。此外，对 IL8/CXCR2 的反应小分子和新型人源化抗体的抑制将与临床和突变亚型，以确定对 IL8/CXCR2 抑制敏感的可靶向亚型。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CXCR2在体内不典型增生/疾病进展启动中的需求两种 MDS 小鼠模型中 CXCR2 的基因缺失。与 NUP-HOXD13 型号一起；一个我们最近开发的 MDS 发育不良和转化的新模型，由杂合子 PU.1 增强子缺失，将用于研究 CXCR2 缺失对疾病引发干细胞和疾病进展。目标 3 将确定以下机制：激活 IL8-CXCR2 通路并确定其在 MDS 中的下游效应子。 IL8 是先天免疫信号级联的已知组成部分，我们将确定上游是否免疫激活剂、IL1RAP、TLR 和 IRAK1/4 正在驱动 IL8/CXCR2 过度激活 MDS 中的途径。我们还将评估 PI3Kinase 的激活和功能意义和 MAP 激酶通路作为 MDS 中 IL8/CXCR2 通路的下游效应器。采取这些研究将共同研究 IL8/CXCR2 通路在 MDS 发病机制中的作用以及确定其作为针对 MDS 中未成熟疾病起始细胞的治疗靶点的潜力。