Role of hormone pathways in chemoprevention for high risk smokers

 描述（由申请人提供）：前吸烟者在戒烟后仍有患肺癌的风险，占新诊断肺癌的50%。烟草暴露导致气道中肿瘤前病变的发展，其经历组织学严重程度的几个阶段，并且在戒烟后可持续存在。伊洛前列素是一种前列环素类似物，主要通过激活过氧化物酶体增殖物激活受体γ（PPARγ）途径发挥作用，在肺癌预防方面取得了进展。在一项随机安慰剂对照试验中，与安慰剂相比，高风险既往吸烟者口服伊洛前列素治疗可改善气道组织学评分和异型增生指数。这一发现表明，使用PPARγ激动剂（如伊洛前列素）可降低气道癌前病变的负担。预测肿瘤前病变持续存在和/或对伊洛前列素耐药的可能性的生物标志物将有助于提示可能与伊洛前列素组合以提高疗效的药物。在这个R21应用中，我们将检查雌激素受体（ER）通路中蛋白质的表达与高危吸烟者中发现的异型增生的严重程度或持续性的相关性（目的1）。雌激素受体（ER）通路与肺癌密切相关，根据我们的初步数据，ER通路是识别气道侵袭性癌前病变的候选通路。我们还将在动物化学预防研究中确定抗雌激素单药和与PPARγ激活联合用药的疗效，以获得支持在人体试验中测试该组合的临床前数据（目的2）。最后我们 将确定ER途径蛋白是否与从正在进行的化学预防临床试验中收集的生物标本中对PPARγ激动剂吡格列酮的耐药性相关，以检测ER途径蛋白作为异型增生持续性和/或对PPARγ激动剂反应的生物标志物的预测价值（目的3）。

 DESCRIPTION (provided by applicant): Former smokers remain at risk for lung cancer after smoking cessation, and make up 50% of new lung cancer diagnoses. Tobacco exposure leads to development of preneoplastic lesions in the airways, which progress through several stages of histologic severity, and which can persist after smoking cessation. Progress in lung cancer prevention was achieved with iloprost, a prostacyclin analog that works mainly through activation of the peroxisomal proliferator-activated receptor γ (PPARγ) pathway. In a randomized placebo-controlled trial, oral iloprost treatment in high-risk former smokers improved both airway histology scores and the dysplasia index compared to placebo. This finding shows that reduction in the burden of airway premalignancy is feasible with PPARγ agonists such as iloprost. Biomarkers that predict potential for persistence of preneoplasias and/or resistance to iloprost would be useful in suggesting agents that might be combined with iloprost to improve efficacy. In this R21 application, we will examine expression of proteins in the estrogen receptor (ER) pathway for association with severity or persistence of dysplasia found in high-risk smokers (Aim 1). The estrogen receptor (ER) pathway has been strongly implicated in lung cancer and is a candidate pathway for identification of aggressive preneoplastic lesions in the airway, based on our preliminary data. We will also determine the efficacy of an anti-estrogen alone and in combination with PPARγ activation in chemoprevention studies in animals, to obtain preclinical data in support of testing this combination in human trials (Aim 2). Finally, we will determine if ER pathway proteins are associated with resistance to the PPARγ agonist pioglitazone in biospecimens collected from an on-going chemoprevention clinical trial, to test the predictive value of ER pathway proteins as biomarkers of dysplasia persistence and/or response to a PPARγ agonist (Aim 3).