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（由适用提供）：急性髓细胞性白血病（AML）是造血系统的毁灭性恶性疾病。 AML的标准治疗方法通常由细胞链滨/基于蒽环类药物的化学疗法组成，但是，只有少数患者使用这种方法治愈。这是需要针对关键白血病途径的新型疗法。 microRNA（miR）是简短的非编码RNA，可调节与正常和白血病细胞关键稳态机制有关的蛋白质的表达。在AML中，不受管制的miR表达参与细胞分化，增殖和生存的造血机制的破坏，这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，我们报告说，miR-155的较高表达预测预后不良，治疗耐药性，并且通常与FLT3内部串联复制（FLT3-ITD）有关，这是一种遗传标记，预测AML预后不良。然而，miR-155提高调节和预后影响与FLT3-ITD无关，而对这种miR表达的放松管制可能代表了公开AML表型的发展的完整“命中”。我们在这里提议剖析miR-155对髓样白血病的作用的机制，并探讨该miR的治疗性靶向如何可能导致AML的临床益处。我们将通过以下特定目的（SAS）：SA1来实现这一总体目标：研究miR-155在髓样室中MiR-155过表达的机制有助于白血病。我们将开发有条件的miR-155转基因鼠模型，其中miR-155将在不同的造血亚群中表达，包括干细胞和更忠实的髓样祖细胞。这些小鼠我们将在形态和功能上被表征。如果未观察到明显的白血病表型，将与FLT3-ITD PRELEKEMIA小鼠交叉； SA2：确定靶向miR-155在AML白血病干细胞（LSC）中的作用和潜在治疗益处。我们将剖析miR-155势LSC自我更新并诱导AML的治疗性的机制； SA3：使用AML的鼠Xenogroticon模型研究合成LNA Antimir-155的药代动力学（PK），药效学（PD）和抗血症活性。我们将对一种新型的合成LNA抗imir-155进行临床前研究，以评估毒性，PK和PD谱，并确定抗Mir的活跃细胞内浓度，从而诱导内源性miR-155的有效下调，并导致miR-155依赖的AML Murine Murine Murine模型中的疾病ELITION的疾病ELITION; SA4：通过对NEDDYDYLATION抑制剂MLN4924进行I期临床试验靶向AML中的miR-155。该临床试验的基本原理是基于我们的数据，表明MLN-4924是MiR-155表达的潜在抑制剂，也是克服MIR-155依赖性治疗耐药性机制的理想候选者。