MicroRNA therapeutics for prostate cancer

前列腺癌的 MicroRNA 疗法

• 批准号: 7909721
• 负责人: Andreas G Bader
• 金额: $ 28.3万
• 依托单位: MIRNA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-22 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909721
• 关键词: Ablation; Address; Animal Model; Area; Blood; Blood Circulation; Cancer Etiology; Cancerous; Carcinoma; Cessation of life; Clinical; Clinical Drug Development; Collagen; Complex; Data; Detection; Development; Diagnostic tests; Disease; Distal; Dose; Drops; Drug Kinetics; Evaluation; FDA approved; Functional RNA; Functional disorder; Gene Expression; Genes; Goals; Grant; Hormones; Human; Image; Incidence; Investigation; Lead; Lobe; Luciferases; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maximum Tolerated Dose; Messenger RNA; Methods; MicroRNAs; Modeling; Neoplasm Metastasis; Nucleic Acids; Operative Surgical Procedures; Organ; Patients; Pharmacodynamics; Phase; Phenotype; Process; Property; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Refractory Disease; Regulator Genes; Resistance; Role; Staging; Survival Rate; Tail; Testing; Therapeutic; Toxicology; Translations; Tumor Suppressor Genes; Uncertainty; Veins; Work; advanced disease; atelocollagen; base; bone; cancer cell; cancer diagnosis; clinically relevant; effective therapy; efficacy testing; implantation; improved; interest; lymph nodes; male; men; mimetics; mouse model; neoplastic cell; novel; pre-clinical; public health relevance; research study; response; tumor; vigilance

DESCRIPTION (provided by applicant): Prostate cancer (PrCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer deaths in males, following only lung cancer. Despite advances leading to more efficient detection, a small but significant number of patients present with advanced disease and/or disease that is hormone resistant or resistant to current therapeutics. Our proposal explores the novel application of small endogenous regulators of gene expression as a new class of therapeutics for prostate cancer. Within the last two decades there has been great interest in microRNAs (miRNAs), small, non-coding RNAs that have been initially identified as regulators of development, and have more recently been demonstrated to have a role in a number of cancers. miRNAs appear to regulate the expression of genes associated with early development and cancer by blocking the translation of target mRNA genes. Their levels are significantly altered in tumors, and their role in regulating the expression of key oncogenes and tumor suppressors suggests this differential expression may be involved in the pathophysiology of cancer. We hypothesize that dysregulated miRNAs are involved in maintaining cancer cell phenotypes and that correcting this dysregulation -- either by miRNA replacement with mimetic or ablation with antisense molecules -- should reverse these phenotypes. The goal of this proposal is to investigate promising miRNAs, delivery methods and delivery molecules that are effective therapies in animal models of human prostate cancer. We have substantial preliminary data that suggest a number of miRNAs may have therapeutic potential. In our investigations, we will test the therapeutic potential of miRNAs on several mouse models of human PrCa, including a model that mimics invasiveness and metastasis. Additionally we will evaluate stabilizing and release compounds that will allow systemic delivery of miRNA therapeutics. We believe these studies will help establish potent anti-cancer miRNAs that can be stabilized and eventually targeted to tumors, allowing delivery of these molecules into the bloodstream. PUBLIC HEALTH RELEVANCE: Advanced prostate cancer continues to be the second leading cause of cancer deaths in males, and is often resistant to conventional therapeutics. Our work may lead to the development of microRNA-based therapies that can be systemically administered and are highly and specifically active towards prostate cancer cells. This will result in a reduced incidence of death from prostate cancer.

描述（由申请人提供）：前列腺癌（PrCa）是男性中最常见的癌症，也是男性癌症死亡的第二大原因，仅次于肺癌。尽管取得了更有效的检测进展，但仍有少数但数量可观的患者出现了晚期疾病和/或激素耐药或对当前治疗方法耐药的疾病。我们的建议是探索小的内源性基因表达调节因子作为前列腺癌治疗新类别的新应用。在过去的二十年里，人们对微小rna （miRNAs）产生了极大的兴趣，微小的非编码rna最初被确定为发育的调节因子，最近被证明在许多癌症中起作用。mirna似乎通过阻断靶mRNA基因的翻译来调节与早期发育和癌症相关的基因的表达。它们的水平在肿瘤中发生显著改变，它们在调节关键癌基因和肿瘤抑制因子表达中的作用表明这种差异表达可能参与了癌症的病理生理。我们假设失调的miRNA参与维持癌细胞表型，纠正这种失调——用模拟miRNA替代或用反义分子消融——应该逆转这些表型。本提案的目标是研究有前途的mirna，传递方法和传递分子，这些mirna是人类前列腺癌动物模型的有效治疗方法。我们有大量的初步数据表明，一些mirna可能具有治疗潜力。在我们的研究中，我们将测试mirna在几种人类PrCa小鼠模型上的治疗潜力，包括模拟侵袭性和转移的模型。此外，我们将评估稳定和释放化合物，使miRNA疗法能够全身递送。我们相信这些研究将有助于建立有效的抗癌mirna，这些mirna可以稳定并最终靶向肿瘤，允许这些分子进入血液。

项目成果

Quantification of therapeutic miRNA mimics in whole blood from nonhuman primates.

• DOI: 10.1021/ac403044t
• 发表时间: 2014-02-04
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Kelnar, Kevin;Peltier, Heidi J.;Leatherbury, Neil;Stoudemire, Jay;Bader, Andreas G.
• 通讯作者: Bader, Andreas G.

miR-34 - a microRNA replacement therapy is headed to the clinic.

• DOI: 10.3389/fgene.2012.00120
• 发表时间: 2012
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Bader AG