Biologic and Therapeutic Significance of miR-155 in AML

miR-155 在 AML 中的生物学和治疗意义

• 批准号: 9010329
• 负责人: CARLO M CROCE
• 金额: $ 57.41万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-03 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010329
• 关键词: 10 year old; Acute Myelocytic Leukemia; Adult Acute Myeloblastic Leukemia; Animal Model; Animals; Anthracyclines; B-Lymphocytes; Biological Assay; Biological Markers; Biology; Blast Cell; Blood Cells; Bone Marrow; Cell Cycle; Cell Differentiation process; Cell Line; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Cytarabine; DNA Methylation; Data; Decitabine; Development; Disease; Dose; Down-Regulation; Drug Combinations; Drug Kinetics; Epigenetic Process; Exhibits; FLT3 gene; Gene Targeting; Genetic; Genetic Markers; Genetically Engineered Mouse; Goals; Hematopoietic; Hematopoietic System; Human; In Vitro; Investigation; Left; Malignant - descriptor; Malignant Neoplasms; MicroRNAs; Minority; Modeling; Molecular; Mus; Mutate; Myelogenous; Normal Cell; Outcome; Pancytopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Phenotype; Plasma; Play; Prevention; Process; Proteins; RNA; Refractory; Relapse; Reporting; Role; Schedule; Spleen; Stem cells; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transgenic Organisms; Treatment outcome; Untranslated RNA; Up-Regulation; Xenograft Model; Xenograft procedure; base; chemotherapy; disease heterogeneity; in vivo; inhibitor/antagonist; leukemia; leukemic stem cell; leukemogenesis; locked nucleic acid; models and simulation; mouse model; new therapeutic target; novel; outcome forecast; overexpression; pre-clinical; preclinical study; progenitor; prognostic; protein expression; public health relevance; self-renewal; small molecule; standard care; targeted treatment; therapeutic target; therapy resistant; treatment response

 DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a devastating malignant disease of the hematopoietic system. Standard treatment for AML generally consists of cytarabine/anthracycline-based chemotherapy, however, only a minority of patients is cured with this approach. Thus, novel therapies targeting key leukemogenic pathways are needed. MicroRNAs (miRs) are short non-coding RNAs that regulate the expression of proteins involved in pivotal homeostatic mechanisms of normal and leukemia cells. In AML, deregulated miR expression is involved in disruption of hematopoietic mechanisms of cell differentiation, proliferation and survival, contributes to the molecular heterogeneity of the disease and impacts on treatment response and outcome. Among other miRs, we reported that higher expression of miR-155 predicts poor outcome, treatment resistance and is often associated with FLT3 internal tandem duplication (FLT3-ITD), a genetic marker predicting poor outcome in AML. However, miR-155 up regulation and prognostic impact is independent from FLT3-ITD and deregulation of this miR expression may represent a complementary "hit" for development of overt AML phenotype. We propose here to dissect the mechanisms through which miR-155 contributes to myeloid leukemogenesis and to explore how the therapeutic targeting of this miR may result in a clinical benefit in AML. We will accomplish this overarching goal through the following specific aims (SAs): SA1: To investigate the mechanisms through which miR-155 over-expression in the myeloid compartment contributes to leukemogenesis. We will develop conditional miR-155 transgenic murine models, where miR-155 will be expressed in different hematopoietic subpopulations, including stem cells and more committed myeloid progenitors. These mice will be characterized morphologically and functionally; if an overt leukemia phenotype is not observed, they will be crossed with the FLT3-ITD preleukemic mice; SA2: To determine the role and potential therapeutic benefit of targeting miR-155 in AML Leukemia Stem Cells (LSCs). We will dissect the mechanisms through which miR-155 potentiates LSC self-renewal and induces treatment resistance in AML; SA3: To investigate in vivo the pharmacokinetic (PK), pharmacodynamic (PD) and antileukemic activity of a synthetic LNA antimiR-155 using murine xenograft models of AML. We will conduct preclinical investigation of a novel, synthetic LNA antimiR-155 to evaluate the toxicity and PK and PD profiles and identify the active intracellular concentrations of the antimiR that induce efficient down-regulation of endogenous miR-155 and results in disease eradication in miR-155-dependent AML murine models; SA4: To target miR-155 in AML by conducting a phase I clinical trial of the neddylation inhibitor MLN4924 in combination with the hypomethylating agent (HMA) decitabine in relapsed/refractory AML patients. The rationale for this clinical trial is based on our data showing that MLN-4924 is a potent inhibitor of miR-155 expression and an ideal candidate to overcome miR-155-dependent mechanisms of treatment resistance.

 描述（由申请人提供）：急性髓性白血病（AML）是一种破坏性的造血系统恶性疾病。AML的标准治疗通常包括基于阿糖胞苷/蒽环类药物的化疗，然而，只有少数患者用这种方法治愈。因此，需要靶向关键白血病发生途径的新疗法。微小RNA（microRNAs，miRs）是一种短的非编码RNA，可调控正常细胞和白血病细胞中重要的稳态机制中的蛋白质的表达。在AML中，失调的miR表达参与细胞分化、增殖和存活的造血机制的破坏，有助于疾病的分子异质性并影响治疗反应和结果。在其他miR中，我们报道了miR-155的较高表达预测不良结局、治疗抗性，并且通常与FLT 3内部串联重复（FLT 3-ITD）相关，FLT 3-ITD是预测AML不良结局的遗传标记。然而，miR-155上调和预后影响独立于FLT 3-ITD，该miR表达的失调可能代表了明显AML表型发展的互补“命中”。我们在此提出剖析miR-155促进髓系白血病发生的机制，并探索这种miR的治疗靶向如何在AML中产生临床益处。我们将通过以下具体目标（SA）实现这一总体目标：SA 1：研究骨髓室中miR-155过表达促进白血病发生的机制。我们将开发条件性miR-155转基因小鼠模型，其中miR-155将在不同的造血亚群中表达，包括干细胞和更定型的髓系祖细胞。将对这些小鼠进行形态学和功能表征;如果未观察到明显的白血病表型，则将其与FLT 3-ITD白血病前期小鼠杂交; SA 2：确定靶向miR-155在AML白血病干细胞（LSC）中的作用和潜在治疗获益。我们将剖析miR-155增强LSC自我更新并诱导AML治疗耐药性的机制; SA 3：使用AML的鼠异种移植模型研究合成LNA antimiR-155的体内药代动力学（PK）、药效学（PD）和抗白血病活性。我们将对新型合成LNA antimiR-155进行临床前研究，以评估毒性以及PK和PD特征，并鉴定antimiR的活性细胞内浓度，其诱导内源性miR-155的有效下调并导致miR-155依赖性AML鼠模型中的疾病根除; SA 4：通过在复发性/难治性AML患者中进行奈丁基化抑制剂MLN 4924联合低甲基化剂（HMA）地西他滨的I期临床试验，靶向AML中的miR-155。这项临床试验的基本原理是基于我们的数据，这些数据表明MLN-4924是一种有效的miR-155表达抑制剂，是克服miR-155依赖性耐药机制的理想候选药物。