PPAR gamma Agonists for Lung Cancer Chemoprevention

 描述(由申请人提供)： 背景：肺癌是美国男性和女性癌症死亡的头号原因，由于军人获得烟草成瘾的高比率，肺癌仍然是退伍军人事务部确定的医疗优先事项。最近的数据显示，现役军人的吸烟率实际上升，退伍军人的吸烟率始终比一般人群高出至少10%(29%对18%)。肺癌的五年存活率仍为16%，这一比率在过去几十年中显示出有限的改善。在退伍军人中，目前只有16%的肺癌被诊断为可治愈阶段。大规模筛查试验(最著名的是国家肺部筛查试验-NLST)已经完成，与胸部X光相比，低剂量CT扫描被证明显著降低了肺癌死亡率(20%)。肺癌的CT筛查已经得到许多团体的认可，一项VA实施研究正在进行中。如果CT筛查在高危人群中被广泛采用(根据NLST的定义)，那么出现可治愈疾病(I期和II期)的患者应该会增加，从而提高总体存活率。存活率的提高将导致RIS的第二原发癌患者数量不断增加。在根治治疗后发生第二次原发肺癌的风险从3%到6%不等。前吸烟者患肺癌的风险也很高，在美国，超过50%的肺癌是在这一群体中确诊的。化学预防药物在这一庞大的高危人群中的潜在临床影响强调了继续研究的必要性。降低肺癌发病率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。我们已经发现，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，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PGI2类似物与转录激活因子PPAR？(过氧化体增殖物激活受体伽马)的作用。这些发现，再加上临床研究发现，在服用PPAR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PPAR激动剂可以预防肺癌。我的VA资助的实验室专注于评估PGI2作为化学预防药物，PGI2水平升高或接受PPAR？激动剂的动物可以防止患肺癌。最重要的是，这导致了一项II期临床试验，显示口服伊洛前列素改善了前吸烟者的支气管内损害。我们目前的人体试验正在评估吡格列酮是高风险的现任和既往吸烟者。建议研究：这项拨款建议推进PPAR激动剂在鳞状细胞肺癌模型中的临床前研究，重点关注PPAR激动剂对肿瘤微环境(TME)和巨噬细胞编程的影响。我们推测，PPAR激活剂(内源性PGI2和吡格列酮)将通过影响炎症细胞募集和表型来阻止支气管内发育不良和肺肿瘤的发展，并将改变TME。将检验以下假设：假设1：PPAR激动剂通过影响肿瘤相关巨噬细胞产生促生长因子和抗生长因子来促进抗肿瘤作用。假设2：选择性PPAR激动剂(内源性前列环素和吡格列酮)通过改变炎症细胞群和巨噬细胞表型来预防小鼠鳞状细胞肺癌和癌前支气管内异型增生的发展。

 DESCRIPTION (provided by applicant): Background: Lung cancer is the number one cause of cancer death in men and women in the United States and remains an identified medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel. Recent data shows an actual increase in smoking rates among active military personnel and smoking rates among Veterans are consistently at least 10% higher than the general population (29% vs. 18%). The five-year survival rate for lung cancer remains 16%, a rate which has shown limited improvement over the last several decades. Among Veterans, only 16% of lung cancer is currently diagnosed at a curable stage. Large-scale screening trials (most notably the National Lung Screening trial - NLST) have been completed, and low dose CT scans were proven to significantly decrease lung cancer mortality (20%) when compared to chest x-ray. CT screening for lung cancer has been endorsed by many groups and a VA implementation study is being conducted. If CT screening is widely adopted in high risk groups (as defined by the NLST), there should be an increase in patients presenting with curable disease (stages I and II), leading to improved overall survival. Improved survival will result in a growing population of patients at ris for second primary lung cancers. The risk of developing a second primary lung cancer after curative treatment ranges from 3-6%. Former smokers are also at high risk of lung cancer, with greater than 50% of lung cancers in the US diagnosed in this group. The potential clinical impact of chemopreventive agents in this large, high-risk population emphasizes the need for continued studies. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemopreventive 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 and key mechanistic studies completed during the last grant cycle have shown that the observed chemoprevention may directly result from PGI2 and PGI2 analogues engaging the transcription activator PPAR¿ (peroxisome proliferator activated receptor gamma). These findings, coupled with clinical studies observing a 33% reduction in lung cancer rates among Veterans taking PPAR¿ agonists for diabetes mellitus, suggest PPAR¿ agonists may prevent lung cancer. My VA funded laboratory has focused on evaluating PGI2 as a chemopreventive agent, and animals with increased levels of PGI2 or receiving PPAR¿ agonists are protected from developing lung cancer. Most importantly, this led to a phase II clinical trial which showed oral iloprost improved endobronchial damage in former smokers. Our current human trial is evaluating pioglitazone is high risk current and former smokers. Proposed Research: This grant proposes to advance pre-clinical studies of PPAR¿ agonists in a squamous cell lung cancer model with a focus on the effects of PPAR¿ agonists on the tumor microenvironment (TME) and macrophage programming. We hypothesize that PPAR¿ activators (endogenous PGI2 and pioglitazone) will chemoprevent the development of endobronchial dysplasia and lung tumors, and will alter the TME by affecting inflammatory cell recruitment and phenotype. The following hypotheses will be tested: Hypothesis 1: PPAR¿ agonists promote anti-tumor effects by influencing the production of pro- and anti- growth factors by tumor associated macrophages. Hypothesis 2: Selective PPAR¿ agonists (endogenous prostacyclin and pioglitazone) chemoprevent the development of murine squamous cell lung cancer and pre-malignant endobronchial dysplasia by altering inflammatory cell populations and macrophage phenotype.