Validation of microRNAs as therapeutic targets in hematological malignancies

验证 microRNA 作为血液恶性肿瘤治疗靶点

基本信息

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
项目类别：
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

项目摘要

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。急性白血病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促进白血病的发生，迄今为止，主要依赖于 mRNA 靶向治疗。然而，当在体内施用时，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。最近发现的细胞内源性 microRNA（miR），即通过与靶 RNA 杂交来调节其翻译速率的短 RNA 序列，为反义 DNA 寡核苷酸提供了一个良好的替代方案。发现特定 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，从而提供了对癌基因或肿瘤抑制基因调节正常的优势，从而似乎促进了相关相关的长期调节。这些结果最近促进了合成制造的 miR 在癌症中的潜在治疗应用的设计。基于 miR 的疗法在小鼠模型中的适用性，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，我们的小组最近确定了 miR-29b 在慢性淋巴细胞表观遗传进展发病机制中的相关性。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 通过调节涉及先天免疫机制的途径、调节 Toll 样受体 4、IL-¿因此，作为基于 miR 的治疗是一种适用且有效的治疗策略的原理证明，我们建议进行临床前体内药代动力学 (PK)、药效学 (PD) 和研究。使用转基因（CLL）和合成的 2-OMemiR-29b 和 2-OMemiR-181a 进行治疗评估，目的是验证药代动力学、药效学和治疗终点异种移植 (AML) 小鼠白血病模型在该项目完成后，我们预计将开始在癌症患者中使用 miR29b 和 miR-181 进行基于 miR 的治疗的初始 I 期研究。