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：
8108056
负责人：
KENNETH K CHAN
金额：
$ 31.64万
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/8108056
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 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. PUBLIC HEALTH RELEVANCE: Only a fraction of patients with acute and chronic leukemia, types of cancer of the bone marrow and blood, survive following current standard chemotherapy treatments and therefore, new treatment approaches are urgently needed. Recently, we and others have discovered natural molecules called microRNAs that regulate expression of functionally relevant genes supporting proliferation, differentiation and death of normal cells and that are either abnormally low or abnormally high in cancer and leukemia cells, thereby initiating and maintaining malignant cell growth. Therefore, we propose here to replace the low levels of natural microRNAs in leukemia cells with synthetic microRNAs as novel therapeutic approach to leukemia patients.

描述（通过应用程序提供）：通过DNA寡脱氧核苷酸（ODN）对癌基因表达的调节，该靶标RNA并导致对相应特定靶蛋白的转化抑制和下调，长期以来一直是癌症中的治疗策略。由于出现非随机分子异常，慢性白血病都被认为适合这种治疗方法，这些异常会导致基因表达降低并直接有助于白血病。迄今为止，靶向mRNA靶向疗法主要基于反义或反互补DNA ODN的方法。但是，当体内给药时，这些分子遭受了多种局限性，这些局限性最近通过修饰这些化合物的骨架结构而部分克服了这些局限性。即使那样，ODN对于目标下调的效率仍然较低。最近发现细胞内源性microRNA（miR）的简短RNA序列通过杂交靶向RNA调节其翻译速率，它提供了反义DNA DNA寡核苷酸的声音替代方法。最近发现，特异性miR水平的改变与恶性转化有关，通过放松靶癌基因或肿瘤抑制基因表达与恶性转化有关。 MIR提供的优势是正常与癌基因或肿瘤抑制基因调控相对应，从而促进了相关靶标的长时间调节，更重要的是，易于靶向一些参与途径的基因调节细胞增殖，分化和存活。这些结果最近促使设计了合成生产的MIR在癌症中的潜在治疗应用的设计。在这里，我们建议研究小鼠模型中基于miR的疗法的临床适用性，在小鼠模型中，特定miR的下调有助于基础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DNMT1，DNMT1，DNMT3A和DNA Hyperor-reiRER和Gene siR，通过调节DNA甲基转移酶来调节DNA甲基转移酶（DNMT1，DNMT1，DNMT1，DNMT1，DNMT1，DNMT1，DNMT1和Gene siR，通过调节），鉴定了miR-29b在慢性淋巴细胞性白血病（CLL）和急性髓性白血病（AML）中的表观遗传进展中的相关性，调节与先天免疫机制有关的途径，调节AML细胞系和原发性爆炸中的受体4，IL-€和miR155表达等收费。因此，作为基于miR的原理治疗的证明，是一种适用有效的治疗策略。因此，我们建议对合成2-omemir-29b和2-omemir-181a进行临床前药代动力学（PK），药代动力学（PD）以及治疗评估，目的是使用Tressemiia（cl）和XERAFT（cl）和XERAFT（cl）和XERAFT（cl）和XERAFT（cl）和XERAFT（cllaft）验证药代动力学，药代动力学和治疗方法。该项目完成后，我们预计在癌症患者中使用miR29b和miR-181使用miR基于miR的治疗的初始I阶段研究开始。公共卫生相关性：只有一小部分患有急性和慢性白血病的患者，骨髓和血液的癌症类型，在当前的标准化疗治疗后生存，因此紧急需要新的治疗方法。最近，我们和其他人发现了称为microRNA的天然分子，这些分子调节了支持正常细胞的增殖，分化和死亡的功能相关基因的表达，并且在癌症和白血病细胞中绝对低或绝对高，从而启动并保持恶性细胞生长。因此，我们在这里提议用合成microRNA作为白血病患者的新型治疗方法来代替白血病细胞中低水平的天然microRNA。