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(申请人提供)：急性髓系白血病(AML)是一种毁灭性的血液系统恶性疾病。AML的标准治疗通常包括以阿糖胞苷/蒽环类药物为基础的化疗，然而，只有少数患者通过这种方法被治愈。因此，需要针对关键的白血病致病途径的新的治疗方法。MicroRNAs(MiRs)是一种短小的非编码RNA，它调节正常细胞和白血病细胞的关键动态平衡机制中涉及的蛋白质的表达。在AML中，miR表达失控参与了细胞分化、增殖和存活等造血机制的破坏，导致了疾病的分子异质性，并影响了治疗反应和预后。在其他miR中，我们报道miR-155的高表达预示着不良预后和治疗耐药，并且经常与Flt3内部串联重复(Flt3-ITD)相关，Flt3-ITD是预测AML不良预后的遗传标志。然而，miR-155的上调和预后的影响是独立于Flt3-ITD的，这种miR表达的解除可能是对AML显性表型发展的一种补充的“打击”。我们建议在这里剖析miR-155促进髓系白血病发生的机制，并探索这种miR的治疗靶点如何在AML中产生临床益处。我们将通过以下特定目标(SA)来实现这一首要目标：SA1：研究miR-155在髓系间室过表达促进白血病发生的机制。我们将建立条件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，包括干细胞和更坚定的髓系祖细胞。这些小鼠将进行形态和功能鉴定；如果没有观察到明显的白血病表型，它们将与Flt3-ITD白血病前期小鼠杂交；SA2：确定靶向miR-155在AML白血病干细胞(LSCs)中的作用和潜在的治疗益处。我们将剖析miR-155促进急性髓系白血病LSC自我更新并诱导治疗耐药的机制；SA3：利用AML小鼠异种移植模型，在体内研究合成的LNA抗itimiR-155的药代动力学(PK)、药效学(PD)和抗白血病活性。我们将进行一项新型的合成LNA抗miR-155的临床前研究，以评估其毒性及PK和PD谱，并确定该抗药的细胞内活性浓度，从而有效下调miR-155的内源性miR-155表达，并最终在依赖miR-155的AML小鼠模型中根除疾病；SA4：通过对复发/难治的AML患者联合应用去甲基化抑制剂MLN4924与低甲基化试剂(HMA)地西他滨进行I期临床试验，靶向治疗AML中的miR-155。这项临床试验的基本原理是基于我们的数据显示，MLN-4924是miR-155表达的有效抑制剂，是克服miR-155依赖的治疗耐药机制的理想候选者。