Therapeutic Micro RNA Strategies for Ovarian Cancer

卵巢癌的 Micro RNA 治疗策略

• 批准号: 7727493
• 负责人: THOMAS C. HAMILTON
• 金额: $ 42.31万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727493
• 关键词: Apoptosis; Biological Markers; Biological Process; Cancer Patient; Cell Proliferation; Clinical Management; Collaborations; Combined Modality Therapy; Cytotoxic Chemotherapy; Data; Detection; Development; Diagnosis; Disease Progression; Dose; Epigenetic Process; Epithelial ovarian cancer; Evolution; Exhibits; Frequencies; Functional RNA; Gene Expression; Genomics; Gynecologic; Human; In Vitro; Instruction; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular Profiling; Molecular Target; Mus; Nucleotides; Oligonucleotides; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Platinum; Platinum Compounds; Play; Predictive Value; Principal Investigator; Proteomics; Recurrent disease; Relative (related person); Reproduction spores; Research; Resistance; Resistance development; Reverse Transcriptase Polymerase Chain Reaction; Role; Specimen; Taxane Compound; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; Transcript; Tumor Suppressor Genes; Tumor Suppressor Proteins; Woman; base; career development; cell growth; chemotherapy; experience; improved; in vivo; mortality; nanoparticle; neoplastic cell; novel; novel therapeutics; optimism; outcome forecast; overexpression; pre-clinical; prognostic; response; restoration; stem; taxane; therapeutic target; therapy resistant; tool; tumor; tumor growth; tumor xenograft

Epithelial ovarian cancer (EOC) is the most frequent cause of gynecologic malignancy-related mortality in women. Although advances in platinum/taxane-based chemotherapy have resulted in improved survival, patients typically experience disease relapse within 2 years of the initial treatment and develop resistance to therapy. Therefore, development of new therapies is a high priority. Molecular targeted drugs hold promise as independent therapeutic agents or chemotherapy response modifiers and could contribute substantial improvements to the outlook of women with EOC. microRNAs (miRNAs) are -22 nucleotide non-coding RNAs, which negatively regulate gene expression in a sequence-specific manner. We have generated the first evidence that miRNAs exhibit genomic alterations at high frequency and their expression is remarkably deregulated in ovarian cancer. This strongly suggests that miRNAs are involved in the initiation and progression of this disease. Indeed, our preliminary studies demonstrate that miRNA is a new class of novel biomarker with strong potential application to EOC in eariy detection, diagnosis and therapeutic response prediction. We hypothesize that miRNAs might serve two roles in the evolution of predictive and therapeutic strategies in EOC. First, it is possible that miRNAs might accurately predict response and resistance to a given chemotherapy. Second, and potentially more exciting in the long term, is the potential that selected mlRNA's might serve as therapeutic tools and/or chemotherapy response modifiers that will offer novel therapeutic opportunities for EOC. We propose the following specific aims to develop miRNA-based therapeutic tools for EOC. Specific Aim 1: Determine the function and therapeutic potential of select miRNAs in vitro. Specific Aim 2: Determine the therapeutic potential of select miRNAs in vivo. Specific Aim 3: Develop one or more constructs directed to specific mlRNA's in Phase l/ll trials. Specific Aim 4: Evaluate the predictive value of miRNAs response and resistance to a given chemotherapy. RELEVANCE (See Instructions): Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women. miRNAs are small non-coding RNAs, which negatively regulate gene expression in a sequence-specific manner. We will conduct a detailed study of miRNA in ovarian cancer, which has not been carried out to date, with the intent to (i) discover new biomarkers for ovarian cancer clinical management or prognosis; (ii) discover novel and important therapeutic targets.

上皮性卵巢癌（EOC）是妇科恶性肿瘤相关死亡的最常见原因。 女性。尽管以铂类/紫杉烷为基础的化疗的进步已经提高了生存率， 患者通常会在初次治疗后 2 年内出现疾病复发，并产生耐药性 治疗。因此，开发新疗法是当务之急。分子靶向药物有希望 作为独立的治疗剂或化疗反应调节剂，可以做出重大贡献 改善患有 EOC 的女性的前景。 microRNA (miRNA) 是-22 核苷酸非编码 RNA，以序列特异性方式负向调节基因表达。我们已经生成了 第一个证据表明 miRNA 表现出高频率的基因组改变，并且它们的表达显着 卵巢癌的失调。这有力地表明 miRNA 参与了启动和 这种疾病的进展。事实上，我们的初步研究表明 miRNA 是一类新的 在 EOC 早期检测、诊断和治疗反应中具有强大应用潜力的生物标志物 预言。我们假设 miRNA 可能在预测和预测的进化中发挥两个作用。 EOC 的治疗策略。首先，miRNA 可能准确预测反应 以及对特定化疗的耐药性。其次，从长远来看可能更令人兴奋的是 选择的mlRNA可能作为治疗工具和/或化疗反应的潜力 将为 EOC 提供新的治疗机会的修饰剂。我们提出以下具体目标 开发基于 miRNA 的 EOC 治疗工具。具体目标 1：确定功能和治疗 选定 miRNA 的体外潜力。具体目标 2：确定选定 miRNA 的治疗潜力 体内。具体目标 3：在 I/II 期试验中开发一个或多个针对特定 mlRNA 的构建体。 具体目标 4：评估 miRNA 对特定化疗反应和耐药性的预测价值。 相关性（参见说明）： 上皮性卵巢癌是女性妇科癌症相关死亡的最常见原因。 miRNA 是小型非编码 RNA，它以序列特异性负向调节基因表达 方式。我们将对卵巢癌中的miRNA进行详细的研究，该研究尚未进行过 日期，目的是 (i) 发现卵巢癌临床管理或预后的新生物标志物； (二) 发现新颖且重要的治疗靶点。