IGF::OT::IGF LUNG CANCER CHEMOPREVENTION BY MICRORNA DELIVERY

通过 MICRORNA 递送进行 IGF::OT::IGF 肺癌化学预防

基本信息

批准号：
9356882
负责人：
MING YOU
金额：
$ 37.76万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9356882
关键词：
Aerosols CCND2 gene Cancer Etiology Cancer Patient Cell Cycle Progression Cessation of life Chemoprevention Chemopreventive Agent Chromosome Mapping Development Disease Early Diagnosis Experimental Models Family Formulation Gene Expression Genetically Engineered Mouse Human Imaging technology Individual Intervention Lesion Lung Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung MicroRNAs Modeling Morbidity - disease rate Mus Oncogenes Patients Pattern Pharmacodynamics Population Premalignant Cell Prevention strategy Process Regimen Regulator Genes Resistance Risk Small RNA Smoke Smoker Staging Structure of parenchyma of lung System Testing Tobacco Tobacco smoke Transcription Repressor/Corepressor Treatment Protocols Tumor Burden Tumor Suppressor Proteins Viral Vector aerosolized base cancer chemoprevention cancer genome cancer therapy carcinogenesis chemical carcinogen chemical carcinogenesis chemotherapeutic agent improved lung carcinogenesis mimetics mortality mouse model non-smoker novel prevent safety testing smoking cessation success treatment response tumor tumor initiation tumor progression

项目摘要

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite improvements in early diagnosis that were made possible by emerging imaging technologies and newly developed targeted chemotherapeutic agents that improve initial treatment responses, the overall 5-year survival for lung cancer patients has remained a dismal 10-15% over the past 3 decades. Although the primary preventive strategy for smoke related diseases is quitting smoking, even after smoking cessation the risk of developing lung cancer remains significantly higher than in non-smokers for 15 years. Thus, the development of chemopreventive strategies that could prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. The population of tobacco smokers and ex-smokers constitutes a readily identifiable group of individuals at risk for lung cancer who would benefit from intervention with chemopreventive regimens. The aim of the proposed study is to evaluate the efficacy of a novel chemopreventive strategy based on the delivery of microRNA mimetics in an experimental model of lung carcinogenesis in mice. MicroRNAs are noncoding small RNAs acting as post-transcriptional repressors and regulators of gene expression. MicroRNAs are grossly dysregulated in human cancers, including lung cancer. The microRNAs that are under-expressed in cancer can be functionally classified as tumor-suppressors while those that are over-expressed act as oncogenes. The let-7 microRNA family is a well characterized family of tumor suppressors whose genes map to different chromosomal regions that are frequently deleted in lung cancer. Let-7 microRNAs negatively regulate multiple oncogenes, including ras, myc, hmga2, and cell-cycle progression regulator genes, such as cdc25a, cdk6, and cyclin D2. . Accordingly, microRNA delivery has been proposed as a new strategy for lung cancer therapy. Previous studies by Kumar et al. (Proc.Natl.Acad.Sci. 105: 3903-8, 2008) and Trang et al. (Oncogene 29: 1580-7, 2010) have shown that intratracheal or intranasal exposure of genetically engineered mice to viral vectors expressing let-7 miRNA mimetics resulted in reduced lung tumor burdens. However, these studies were done in genetically engineered mouse models that developed highly aggressive tumors more relevant for a treatment regimen. In addition, Kumar et al. noted that some tumors emerged that were resistant to the let-7 miRNA. The success of this approach may thus be limited by the fact that the patterns of altered microRNAs continuously change due to the instability of cancer cell genome. In healthy and premalignant cells, the alterations in microRNA expression may be less unstable and more likely to be reversible with agent treatment. Thus, testing of let-7 miRNA in murine models of chemical carcinogenesis utilizing chemical carcinogens implicated in tobacco smoke-induced disease would be important for determining the potential use of these agents in prevention strategies. This model develops tumors with a longer latency and allows an assessment of agent effects at the earliest stages of tumor initiation and progression. It will be important to develop an intranasal or aerosol delivery system that could be subsequently tested for safety and efficacy of microRNA administration aimed at preventing lung cancer by blocking the progression of the carcinogenesis process.

肺癌是全球癌症相关死亡的主要原因。尽管新兴成像技术和新开发的靶向化疗药物改善了初始治疗反应，使得早期诊断得以改善，但在过去 30 年中，肺癌患者的总体 5 年生存率仍然只有 10-15%。尽管吸烟相关疾病的主要预防策略是戒烟，但即使戒烟后，15年内患肺癌的风险仍然显着高于不吸烟者。因此，开发可以防止肺部病变进展为恶性肿瘤的化学预防策略将降低这种致命疾病造成的死亡率和发病率。吸烟者和戒烟者群体构成了易于识别的肺癌风险人群，他们将受益于化学预防方案的干预。本研究的目的是评估一种基于 microRNA 模拟物在小鼠肺癌发生实验模型中递送的新型化学预防策略的功效。 MicroRNA 是非编码小 RNA，充当转录后抑制因子和基因表达调节因子。 MicroRNA 在包括肺癌在内的人类癌症中严重失调。癌症中表达不足的 microRNA 在功能上可归类为肿瘤抑制基因，而过度表达的 microRNA 则可作为癌基因。 let-7 microRNA 家族是一个特征明确的肿瘤抑制家族，其基因映射到肺癌中经常被删除的不同染色体区域。 Let-7 microRNA 负向调节多种癌基因，包括 ras、myc、hmga2 和细胞周期进程调节基因，如 cdc25a、cdk6 和 cyclin D2。。因此，microRNA递送已被提议作为肺癌治疗的新策略。 Kumar 等人之前的研究。 (Proc.Natl.Acad.Sci. 105: 3903-8, 2008) 和 Trang 等人。 (Oncogene 29: 1580-7, 2010) 表明，基因工程小鼠气管内或鼻内暴露于表达 let-7 miRNA 模拟物的病毒载体，可减少肺肿瘤负荷。然而，这些研究是在基因工程小鼠模型中进行的，这些模型产生了与治疗方案更相关的高度侵袭性肿瘤。此外，库马尔等人。指出一些肿瘤对 let-7 miRNA 具有抗性。因此，这种方法的成功可能会受到以下事实的限制：由于癌细胞基因组的不稳定性，改变的 microRNA 的模式不断变化。在健康细胞和癌前细胞中，microRNA 表达的变化可能不太不稳定，并且更有可能通过药物治疗而逆转。因此，利用与烟草烟雾诱发的疾病有关的化学致癌剂在化学致癌的小鼠模型中测试let-7 miRNA对于确定这些药物在预防策略中的潜在用途非常重要。该模型产生具有较长潜伏期的肿瘤，并允许在肿瘤发生和进展的最早阶段评估药物效果。开发一种鼻内或气雾剂输送系统非常重要，该系统可以随后测试 microRNA 给药的安全性和有效性，旨在通过阻止癌变过程的进展来预防肺癌。