MicroRNA therapeutics for prostate cancer

描述（由申请人提供）：前列腺癌（PrCa）是男性中最常诊断的癌症，也是男性癌症死亡的第二大原因，仅次于肺癌。尽管取得了导致更有效检测的进展，但仍有少量但显著数量的患者患有晚期疾病和/或激素抗性或对当前治疗剂具有抗性的疾病。我们的提案探索了小的内源性基因表达调节剂作为前列腺癌的新一类疗法的新应用。在过去的二十年里，人们对microRNA（miRNAs）产生了极大的兴趣，这些小的非编码RNA最初被鉴定为发育的调节因子，最近被证明在许多癌症中发挥作用。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显著改变，并且它们在调节关键癌基因和肿瘤抑制因子的表达中的作用表明这种差异表达可能参与癌症的病理生理学。我们假设失调的miRNA参与维持癌细胞表型，并且通过用模拟物替换miRNA或用反义分子消融来纠正这种失调应该逆转这些表型。该提案的目标是研究有前途的miRNAs，递送方法和递送分子，这些分子是人类前列腺癌动物模型的有效疗法。我们有大量的初步数据表明，许多miRNAs可能具有治疗潜力。在我们的研究中，我们将在几种人类PrCa小鼠模型上测试miRNA的治疗潜力，包括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，这将允许miRNA治疗剂的全身递送。我们相信这些研究将有助于建立有效的抗癌miRNAs，这些miRNAs可以稳定并最终靶向肿瘤，从而将这些分子输送到血液中。 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，并且通常对常规疗法具有抗性。我们的工作可能会导致基于microRNA的疗法的发展，这些疗法可以全身施用，并且对前列腺癌细胞具有高度和特异性的活性。这将导致前列腺癌死亡率降低。

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.