PPAR gamma Agonists for Lung Cancer Chemoprevention

描述(由申请人提供)： 背景：肺癌是一个重大的医学问题，是美国和世界范围内男性和女性癌症死亡的头号原因。肺癌是退伍军人事务部的医疗优先事项，因为军人的烟草成瘾率很高，而且最近的数据显示，烟草使用率高于普通公众。主要退伍军人组织(AMVETS、残疾美国退伍军人、瘫痪美国退伍军人和外国战争退伍军人)支持增加退伍军人管理局早期肺癌研究的资金。虽然大规模的筛查试验正在进行中，但还没有既定的筛查试验，而且有明显的少数患者(25%)患有可手术治愈的疾病(I期和II期)。肺癌的累积五年存活率为15%，这一比率在过去几十年中显示出有限的改善。大多数肺癌现在都是在前吸烟者中被诊断出来的，这强调了在这一庞大的高危人群中进行有效化学预防的必要性。在降低肺癌发病率方面取得的成功不仅取决于吸烟的预防和戒烟，还取决于有效的化学预防策略。已完成的工作：前列环素(Prostaglandin I2，PGI2)是一种天然存在的二十烷类化合物，具有抗炎和抗转移特性，并对肿瘤生长具有抑制作用。我们发现，这些二十烷类化合物的平衡在肺肿瘤的发生中起着关键作用。我的VA资助的实验室专注于评估PGI2作为化学防御剂，具有选择性肺PGI过度表达的转基因小鼠在几种不同的小鼠腺癌模型中受到化学保护(包括化学和烟草烟雾暴露)。我们已经将我们的研究扩展到接受伊洛前列素(一种口服PGI2类似物)的动物，并显示了类似的化学预防作用。最重要的是，最近的一项II期临床试验显示，口服伊洛前列素改善了既往吸烟者的支气管内损害。在上一次赠款周期中完成的关键机制研究表明，所观察到的化学预防可能直接源于PGI2和伊洛前列斯特激活转录激活因子PPARg(过氧化体增殖物激活的受体伽马)。这些发现，再加上最近的临床研究，在服用PPARg激动剂治疗糖尿病的退伍军人中，肺癌发病率降低了33%，这表明PPARg激动剂可以预防肺癌。建议研究：这项拨款建议推进PPARg激动剂在鳞状细胞肺癌模型和烟草烟雾暴露模型中的临床前研究。我们假设PPARg激活剂(伊洛前列素和吡格列酮)将通过影响炎症细胞的募集和表型来阻止支气管内发育不良和肺肿瘤的发展，并改变肿瘤的微环境。将检验以下假设：假设1：PPARG激动剂(伊洛前列素和吡格列酮)将在鳞状细胞肺癌的小鼠模型中预防鳞状细胞肺癌和癌前支气管腔内异型增生的发生。假设2：在烟草烟雾模型中，PPARG激动剂将化学预防肺癌和癌前病变，并改变炎症细胞的募集和激活。

DESCRIPTION (provided by applicant): Merit Review Abstract: Background: Lung cancer is a major medical problem and the number one cause of cancer death in men and women in the US and worldwide. Lung cancer is a medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel and recent data shows tobacco use rates higher than that of the general public. Leading Veterans organizations (AMVETS, Disabled American Veterans, Paralyzed Veterans of America, and Veterans of Foreign Wars) have supported increased funding for early lung cancer research at the Veterans Administration. While large-scale screening trials are in progress, there are no established screening tests, and a distinct minority of patients (<25%) present with surgically curable disease (stages I and II). The cumulative five-year survival rate for lung cancer is 15%, a rate which has shown limited improvement over the last several decades. The majority of lung cancers are now diagnosed in former smokers, emphasizing the need for effective chemoprevention in this large, at-risk population. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemo-preventive strategies. Work Accomplished: Prostacyclin (prostaglandin I2, PGI2) is a naturally occurring eicosanoid that possesses anti-inflammatory and anti-metastatic properties, as well as a suppressive role in tumor growth. We have found that the balance of these eicosanoids is pivotal in lung tumorigenesis. My VA funded laboratory has focused on evaluating PGI2 as a chemo-preventive agent, and transgenic mice with selective pulmonary PGIS over-expression are chemoprotected in several distinct murine adenocarcinoma models (including both chemical and tobacco-smoke exposure). We have extended our studies to animals receiving Iloprost (an oral PGI2 analogue) and have shown similar chemoprevention. Most importantly, a recent phase II clinical tria showed oral iloprost improved endobronchial damage in former smokers. Key mechanistic studies completed during the last grant cycle have shown that the observed chemoprevention may directly result from PGI2 and iloprost activating the transcription activator PPARg (peroxisome proliferator activated receptor gamma). These findings, coupled with recent clinical studies observing a 33% reduction in lung cancer rates among Veterans taking PPARg agonists for diabetes mellitus, suggest PPARg agonists may prevent lung cancer. Proposed Research: This grant proposes to advance pre-clinical studies of PPARg agonists in a squamous cell lung cancer model and a tobacco smoke exposure model. We hypothesize that PPARg activators (iloprost and pioglitazone) will chemoprevent the development of endobronchial dysplasia and lung tumors, and will alter the tumor microenvironment by affecting inflammatory cell recruitment and phenotype. The following hypotheses will be tested: Hypothesis 1: PPARg agonists (iloprost and pioglitazone) will chemoprevent the development of squamous cell lung cancer and pre-malignant endobronchial dysplasia in a murine model of squamous cell lung cancer. Hypothesis 2: PPARg agonists will chemoprevent lung cancer and premalignant lesions in a tobacco smoke model and alter inflammatory cell recruitment and activation.