PPAR gamma Agonists for Lung Cancer Chemoprevention

描述（由申请人提供）： Merit评审摘要：背景资料：肺癌是一个主要的医学问题，也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一个医疗优先事项，因为军事人员的烟草成瘾率很高，最近的数据显示，烟草使用率高于一般公众。领先的退伍军人组织（AMVETS，美国残疾退伍军人，美国瘫痪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，但没有建立筛选测试，并且明显少数患者（<25%）存在手术可治愈的疾病（I期和II期）。肺癌的累积五年存活率为15%，在过去几十年中，这一比率的改善有限。现在大多数肺癌都是在前吸烟者中诊断出来的，这强调了在这个庞大的高危人群中进行有效化学预防的必要性。提高降低肺癌发病率的成功率不仅取决于预防吸烟和戒烟，还取决于有效的化学预防策略。完成的工作：前列环素（前列腺素I2，PGI2）是一种天然存在的类二十烷酸，具有抗炎和抗转移特性，以及抑制肿瘤生长的作用。我们发现这些类二十烷酸的平衡在肺肿瘤发生中是关键的。我的VA资助的实验室专注于评估PGI2作为化学预防剂，选择性肺PGIS过表达的转基因小鼠在几种不同的小鼠腺癌模型（包括化学和烟草烟雾暴露）中受到化学保护。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，并显示出类似的化学预防作用。最重要的是，最近的II期临床试验表明，口服伊洛前列素改善了前吸烟者的支气管内损伤。在上一个资助周期完成的关键机制研究表明，观察到的化学预防可能直接由PGI2和伊洛前列素激活转录激活因子PPARg（过氧化物酶体增殖物激活受体γ）引起。这些发现，再加上最近的临床研究观察到33%的降低肺癌率退伍军人服用PPARg激动剂治疗糖尿病，表明PPARg激动剂可能会预防肺癌。拟议研究：该资助计划用于推进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）将化学预防支气管内发育不良和肺肿瘤的发生，并通过影响炎性细胞募集和表型改变肿瘤微环境。将检验以下假设：假设1：PPARg激动剂（伊洛前列素和吡格列酮）将在鳞状细胞肺癌小鼠模型中化学预防鳞状细胞肺癌和癌前支气管内发育不良的发生。假设二：PPARg激动剂将在烟草烟雾模型中化学预防肺癌和癌前病变，并改变炎性细胞的募集和活化。 公共卫生相关性： 肺癌是美国男性和女性癌症死亡的头号原因，也是退伍军人事务部的医疗优先事项，因为军人吸烟成瘾率很高。虽然正在进行大规模的筛查试验，但没有建立肺癌早期检测的筛查试验，只有16%的肺癌退伍军人被诊断为手术可治愈的疾病（I期和II期）。临床经验表明，大多数肺癌是在以前吸烟者中诊断出来的，这强调了在这个庞大的高危人群中进行有效化学预防的必要性。我们提出了新的实验，涉及化学预防剂，已被证明可以改善吸烟引起的气道损伤，并与退伍军人群体的肺癌发病率较低。我们的研究结果将有助于更好地了解肺癌的早期阶段，并可能导致未来的人类化学预防试验。

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. PUBLIC HEALTH RELEVANCE: Lung cancer is the number one cause of cancer death in men and women in the United States and a medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel. While large-scale screening trials are being conducted, there are no established screening tests for the early detection of lung cancer, and only 16% of Veterans with lung cancer are diagnosed with surgically curable disease (stages I and II). Clinical experience has shown that the majority of lung cancers are diagnosed in former smokers, emphasizing the need for effective chemoprevention in this large, at-risk population. We propose novel experiments involving chemo-preventive agents that have been shown to improve smoking induced airway damage and are associated with lower lung cancer rates in Veteran populations. Our results will lead to a better understanding of the early stages of lung cancer and may lead to future human chemoprevention trials.