Engineering ex vivo models of lung cancer and chemoprevention

项目总结 肺癌是一种特别具有破坏性的诊断，占美国所有癌症死亡人数的24% 各州。在美国，每2.3分钟就会出现一例新的肺癌诊断，其中超过一半 诊断是在前吸烟者身上进行的。这一可识别的高危人群是化学预防的理想目标。 阻止肺癌的出现是减轻肺癌死亡负担的关键，然而， 预防药物的研究依赖于动物模型，而且成本高、耗时长，需要大量的实验 关于动物的。精密切割肺切片(PCL)通过保留生活的复杂性来解决这些挑战 组织，同时使动物外的疾病研究成为可能。这些小鼠肺组织的薄片生长在 DISH可用于研究致癌的暴露和测试预防癌症的药物。PCL有 由于动物外部组织切片的分解，尚未用于早期肺癌的研究。我们 已经开发出一种新的方法，使用生物工程材料来延长肺组织的寿命 长在老鼠外面的。我们建议使用这个模型来研究早期肺癌和预防药物。我们 将优化我们的生物工程PCLS的条件，以进一步增加肺组织生长的稳定性 在一只老鼠外面。我们将把PCL暴露在烟草致癌物中，以诱导肺细胞发生异常，这些细胞 已知先于小鼠的肺部肿瘤。当我们可以在PCLS中诱导早期肺癌时，我们将测试 已知可预防小鼠肺癌发展的药物的效果，看看它们是否也能预防或逆转 PCLS早期肺癌的发生发展。我们还将测试四种新出现的预防药物，以验证 利用我们的系统筛选新化合物的功效。我们的生物工程系统可能有一个 对我们如何产生支持肺癌预防药物临床试验的数据产生重大影响。通过 从一个小鼠的肺中制作许多单独的切片，将减少动物的数量和成本 需要测试多种条件和药物的研究。这种方法还将显著缩短时间。 需要通过研究培养皿中的活组织来研究预防药物的作用方式及其对肺部生物学的影响 而不是在动物身上。为老鼠组织开发这一系统将为使用人类组织奠定基础 组织。这将直接影响有肺癌风险的患者，并改善他们的临床筛查方式。 试验或个别治疗。有了这个探索性的奖项，我们预计将提供一种新的早期肺模型 癌症将支持进一步资助高级研究，从而增加对预防的使用 在高危人群中使用药物和降低肺癌死亡率。

PROJECT SUMMARY Lung cancer is a particularly devastating diagnosis accounting for 24% of all cancer deaths in the United States. A new lung cancer diagnosis occurs every 2.3 minutes in the U.S. and more than half of these diagnoses are in former smokers. This identifiable high-risk population is an ideal target for chemoprevention. Intercepting the emergence of lung tumors is key to reducing the burden of lung cancer mortality, however, studies on prevention drugs rely on animal models and are costly, time consuming, and require large numbers of animals. Precision-cut lung slices (PCLS) address these challenges by retaining the complexity of living tissue while enabling disease studies outside the animal. These thin slices of mouse lung tissue grown in a dish can be used for studying exposures that cause cancer and testing drugs that prevent cancer. PCLS have not yet been used for studies of early lung cancer due to breakdown of the tissue slices outside the animal. We have developed a new approach that uses bioengineered materials to support extended life of lung tissue grown outside a mouse. We propose to use this model to study early lung cancer and prevention drugs. We will optimize the conditions of our bioengineered PCLS to further increase the stability of lung tissue grown outside a mouse. We will expose PCLS to tobacco carcinogens to induce abnormalities in lung cells that are known to precede lung tumors in mice. When we can induce early lung cancer in the PCLS, we will test the effects of drugs known to prevent lung tumor development in mice to see if they also prevent or reverse development of early lung cancer in PCLS. We will also test four emerging prevention drugs to validate the use of our system for screening the efficacy of new compounds. Our bioengineered system could have a significant impact on how we generate the data supporting clinical trials of lung cancer prevention drugs. By making many individual slices from a single mouse lung, it will reduce the number of animals and cost of the studies required to test multiple conditions and drugs. This approach will also significantly shorten the time needed to study how prevention drugs work and their impact on lung biology by studying live tissue in a dish rather than in an animal. Developing this system for mouse tissue will build the foundation for using human tissue. This will directly impact patients at risk of lung cancer and improve how they are screened for clinical trials or individual treatments. With this exploratory award, we anticipate delivering a new model of early lung cancer that will support further funding for advanced studies, leading to an increase in the use of prevention drugs in high risk populations and a reduction in lung cancer mortality.