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: 8627134
• 负责人: GUIDO MARCUCCI
• 金额: $ 30.69万
• 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/8627134
• 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（由申请人提供）：通过靶向信使RNA的DNA寡脱氧核苷酸（ODN）调节癌基因表达并导致相应特定靶蛋白的翻译抑制和下调，长期以来一直被视为癌症的治疗策略。慢性和急性白血病都被认为适合这种治疗方法，因为非随机分子异常的发生会解除基因表达的调节并直接导致白血病发生。迄今为止，mRNA 靶向治疗主要依赖于反义或反向互补 DNA ODN 方法。然而，当体内给药时，这些分子受到多种限制，最近通过修饰这些化合物的主链结构部分克服了这些限制。即便如此，ODN 下调目标的效率总体上仍然较低。最近发现的细胞内源性 microRNA (miR) 是一种短 RNA 序列，通过与靶 RNA 杂交来调节其翻译速率，为反义 DNA 寡核苷酸提供了一种合理的替代方案。最近的发现支持了这一概念，即特定 miR 水平的改变在机制上与通过靶癌基因或肿瘤抑制基因表达的失调而发生的恶性转化相关。 MiR 具有作为癌基因或肿瘤抑制基因调节的正常对应物的优势，因此似乎可以促进相关靶标的长期调节，更重要的是，它可以同时靶向参与调节细胞增殖、分化和存活途径的多个基因。这些结果最近促使人们设计合成制造的 miR 在癌症中的潜在治疗应用。在这里，我们建议在小鼠模型中研究基于 miR 的体内疗法的临床适用性，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。我们的小组最近通过调节 DNA 甲基转移酶 [DNMT1、DNMT3A 和 DNMT3B]、DNA 高甲基化和基因沉默，确定了 miR-29b 在慢性淋巴细胞白血病 (CLL) 和急性髓系白血病 (AML) 表观遗传进展发病机制中的相关性，以及 miR-181a 在肿瘤抑制活性中的相关性。 调节涉及先天免疫机制的途径，调节 AML 细胞系和原代母细胞中的 Toll 样受体 4、IL-¿ 和 miR155 表达。因此，作为原理证明，基于 miR 的治疗是一种适用且有效的治疗策略。因此，我们建议使用转基因（CLL）和异种移植（AML）小鼠白血病模型对合成的2-OMemiR-29b和2-OMemiR-181a进行临床前体内药代动力学（PK）、药效学（PD）和治疗评估，以验证药代动力学、药效学和治疗终点。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 的治疗的初始 I 期研究。