MicroRNA therapeutics for prostate cancer

描述(申请人提供)：前列腺癌(PrCa)是男性最常见的癌症，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，但仍有少量但相当数量的患者患有晚期疾病和/或激素抵抗或对当前治疗方法耐药的疾病。我们的提案探索了基因表达的内源性小调节剂作为前列腺癌新的治疗方法的新应用。在过去的二十年里，人们对microRNAs(MiRNAs)产生了极大的兴趣，这是一种小的、非编码的RNA，最初被确定为发育的调节因子，最近被证明在一些癌症中发挥了作用。MiRNAs似乎通过阻止靶基因的翻译来调节与早期发育和癌症相关的基因的表达。在肿瘤中，它们的水平发生了显著的变化，它们在调节关键癌基因和肿瘤抑制因子的表达方面的作用表明，这种差异表达可能参与了癌症的病理生理学。我们假设，失调的miRNAs参与维持癌细胞的表型，纠正这种失调--无论是用模拟的miRNA替换还是用反义分子消融--应该会逆转这些表型。这项提议的目标是研究在人类前列腺癌动物模型中有希望的miRNAs、递送方法和递送分子是有效的治疗方法。我们有大量的初步数据表明，一些miRNAs可能具有治疗潜力。在我们的研究中，我们将在几个人类PrCa的小鼠模型上测试miRNAs的治疗潜力，包括一个模拟侵袭和转移的模型。此外，我们将评估稳定和释放化合物，使其能够系统地输送miRNA治疗药物。我们相信这些研究将有助于建立有效的抗癌miRNAs，这种miRNAs可以稳定下来，并最终靶向肿瘤，使这些分子能够进入血液。 公共卫生相关性：晚期前列腺癌仍然是男性癌症死亡的第二大原因，而且往往对传统疗法耐药。我们的工作可能导致基于microRNA的疗法的开发，这种疗法可以系统地给药，并且对前列腺癌细胞高度和特异地活跃。这将导致前列腺癌死亡率的降低。

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.