Validation of microRNAs as therapeutic targets in hematological malignancies

验证 microRNA 作为血液恶性肿瘤治疗靶点

• 批准号: 8458884
• 负责人: KENNETH K CHAN
• 金额: $ 29.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458884
• 关键词: Aberrant DNA Methylation; Acute Myelocytic Leukemia; Acute leukemia; Address; Animals; Antisense DNA; Biological; Blast Cell; Blood; Blood Cells; Bone Marrow; Cancer Patient; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Complementary DNA; DNA; DNA Methyltransferase; DNA Modification Methylases; Dose; Down-Regulation; Drug Kinetics; Enzymes; Epigenetic Process; Functional RNA; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Goals; Hematologic Neoplasms; Human; Hypermethylation; Individual; Investigation; Maintenance; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; Methods; Methylation; MicroRNAs; Modeling; Molecular Abnormality; Mus; Myelogenous; Natural Immunity; Normal Cell; Oligonucleotides; Oncogenes; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Plasma; Prevention; Proteins; RNA; RNA Sequences; Resistance; Role; Schedule; Spleen; Structure; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Organisms; Translational Repression; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; Validation; Vertebral column; Xenograft procedure; analytical method; base; cancer cell; cancer type; cell growth; chemotherapy; chronic leukemia; clinical application; clinical efficacy; design; in vivo; leukemia; leukemogenesis; mouse model; novel; novel therapeutic intervention; novel therapeutics; phase 1 study; pre-clinical; promoter; public health relevance; sound; therapeutic evaluation; therapeutic target; toll-like receptor 4; tumorigenesis

DESCRIPTION (provided by applicant): Modulation of oncogene expression by DNA oligodeoxynucleotides (ODNs) that target messenger RNAs and result in translational inhibition and down-regulation of the corresponding specific target proteins has long been pursued as a therapeutic strategy in cancer. Both chronic and acute leukemia's have been regarded as suitable for this therapeutic approach because of the occurrence of non-random molecular abnormalities that de-regulate gene expression and directly contribute to leukemogenesis. To date mRNA targeted therapies have relied mostly on antisense or reverse complementary DNA ODN-based approaches. When administered in vivo, however, these molecules suffer from a variety of limitations that have recently been partially overcome by modifying the backbone structure of these compounds. Even then, the efficiency of ODNs for target downregulation remains overall low. The recent discovery of cellular endogenous microRNAs (miRs), short RNA sequences that by hybridizing to target RNAs regulate their translation rate, has offered a sound alternative to the antisense DNA oligonucleotides. This concept has been supported by the recent discovery that alterations in the levels of specific miRs are mechanistically relevant to malignant transformation through deregulation of target oncogene or tumor suppressor gene expression. MiRs offer the advantage of being normal counterparts to oncogene or tumor suppressor gene regulation and thereby appear to promote prolonged modulation of the relevant targets and more importantly to target simultaneously several genes involved in pathways regulating cell proliferation, differentiation and survival. These results have recently prompted the design of potential therapeutic applications of synthetically manufactured miRs in cancer. Here, we propose to investigate the clinical applicability of miR-based therapies in-vivo in mouse models where downregulation of specific miRs contributes to malignant transformation and/or aggressive phenotypes of the underlying leukemia. Our group has recently identified relevance of miR-29b in the pathogenesis of epigenetic progression in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) through modulation of DNA methyltransferases [DNMT1, DNMT3A and DNMT3B], DNA hypermethylation and gene silencing and miR-181a in tumor suppressor activity by modulating pathways involved in mechanisms of innate immunity, regulating Toll like receptor 4, IL-¿ and miR155 expression in AML cell lines and primary blasts. Therefore, as proof of principle miR-based therapy is an applicable and effective therapeutic strategy. Hence, we propose to perform preclinical in-vivo pharmacokinetic (PK), pharmacodynamic (PD), and therapeutic evaluation of synthetic 2-OMemiR-29b and 2-OMemiR-181a with the goal to validate the pharmacokinetic, pharmacodynamic and therapeutic endpoints, using transgenic (CLL) and xenograft (AML) murine leukemia models. At completion of this project, we anticipate the beginning of initial phase I studies with miR based therapy using miR29b and miR-181 in cancer patients.

描述(申请人提供)：以信使RNA为靶标的DNA寡核苷酸(ODN)调节癌基因的表达，并导致相应的特定靶蛋白的翻译抑制和下调，长期以来一直是癌症的一种治疗策略。慢性白血病和急性白血病都被认为适合这种治疗方法，因为它会发生非随机的分子异常，使基因表达失控，并直接导致白血病的发生。到目前为止，信使核糖核酸靶向治疗主要依赖于基于反义或反向互补DNA ODN的方法。然而，当在体内给药时，这些分子受到各种限制，最近通过改变这些化合物的主干结构部分克服了这些限制。即便如此，ODN对目标下调监管的效率总体上仍然很低。最近发现的细胞内源性microRNAs(MiRs)是一种通过与靶RNA杂交来调节其翻译速率的短RNA序列，它为反义DNA寡核苷酸提供了一种良好的替代方案。最近的一项发现支持了这一概念，即特异性MIR水平的改变与靶癌基因或肿瘤抑制基因表达的解除调控与恶性转化具有机械相关性。MIR具有癌基因或抑癌基因调控的正常对应物的优势，从而促进相关靶点的延长调节，更重要的是同时靶向参与调节细胞增殖、分化和生存途径的几个基因。这些结果最近促使了人工制造的MIR在癌症中的潜在治疗应用的设计。在此，我们建议在小鼠模型中研究基于miR的治疗的临床适用性，其中特定miR的下调有助于潜在白血病的恶性转化和/或侵袭性表型。我们的团队最近发现miR-29b与慢性淋巴细胞白血病(CLL)和急性髓系白血病(AML)表观遗传进展的发病机制有关，它通过调节DNA甲基转移酶[DNMT1、DNMT3a和Dnmt3b]、DNA高甲基化和基因沉默以及miR-181a在肿瘤抑制活性中的作用，通过调节参与天然免疫机制的途径，调节AML细胞株和原代母细胞中Toll样受体4、IL-β和miR155的表达。因此，作为原则的证明，基于miR的治疗是一种适用且有效的治疗策略。因此，我们建议进行临床前体内药代动力学(PK)、药效学(PD)和治疗评价，目的是利用转基因(CLL)和异种移植(AML)小鼠白血病模型验证药代动力学、药效学和治疗终点。在该项目完成后，我们预计将开始在癌症患者中使用miR29b和miR-181进行基于miR的治疗的第一阶段研究。