Exisulind for Chemoprevention of Lung Cancer

描述（由申请人提供） 肺癌是美国癌症死亡的主要原因。初级治疗的治愈率很低（约15%）。迫切需要开发化合物，可以预防有吸烟史和其他与肺癌风险增加相关因素的个体的疾病。许多化合物已被测试，但迄今为止的试验并没有导致肺癌发病率的降低。事实上，两个大规模的化学预防试验，评估β-胡萝卜素在活跃和前吸烟者，导致肺癌的发病率和死亡率增加。近年来，肺癌化学预防的重点已转向使用炎症反应通路抑制剂和生长因子信号通路抑制剂的研究。已经开发了一类新的诱导细胞凋亡的药物。舒林（Aptosyn）是这类药物中的第一种，它通过减少人类腺瘤性息肉的数量而在结肠直肠癌的化学预防中显示出希望。在动物研究中，这种药剂导致致癌物诱发的肺癌减少。为了测试这种药物在肺癌预防中的临床效用，我们建议在前吸烟者中进行双盲，安慰剂对照，随机临床疗效试验。受试者将根据气道阻塞、完全切除的I期非小细胞肺癌既往史和支气管活检的组织病理学，按肺癌风险分层。他们将以2：1的比例随机分配至药物组和安慰剂组。肺癌的替代标志物，增殖标志物Ki-67，将用作主要终点。我们和其他人之前和目前研究的其他标志物（MCM 2、hnRNP、细胞凋亡、细胞因子反应谱、（epi）遗传改变、形态学）将作为替代试验终点进行探索。将以每日500 mg的剂量口服舒林6个月。93名可评估的参与者随机接受依昔舒林，该研究将有80%的把握度检测到治疗导致的平均Ki-67标记指数下降50%或更多。由于我们预计损耗率为25%，因此我们计划在4年内共入组186例受试者。考虑到我们机构已经参与早期检测试验的合格受试者数量，我们相信这项拟议研究的目标可以在5年的资助期间实现。这些研究所产生的数据将是重要的未来决策的大规模化学预防试验使用疾病的发病率和死亡率作为终点。

DESCRIPTION (provided by applicant) Lung cancer is the leading cause of cancer death in the United States. Cure rates from primary treatment are low (approximately 15%). There is an urgent need to develop compounds, which can prevent the disease in individuals with a history of cigarette smoking and other factors associated with increased lung cancer risk. A number of compounds have been tested but trials to date have not resulted in a decrease of lung cancer incidence. In fact, two large-scale chemoprevention trials that evaluated beta-carotene in active and former smokers, resulted in an increase of incidence and mortality from lung cancer. Recently, the focus of lung cancer chemoprevention has shifted towards investigations using inhibitors of inflammatory response pathways and inhibitors of growth factor signaling pathways. A novel class of agents has been developed that induce apoptosis. Exisulind (Aptosyn) is the first agent in this class, and it has shown promise in chemoprevention of colorectal carcinoma by reducing the number of size of adenomatous polyps in humans. In animal studies, this agent has resulted in a reduction of carcinogen-induced lung cancer. To test the clinical utility of this agent in lung cancer prevention, we propose to perform a double-blind, placebo-controlled, randomized, clinical efficacy trial in former smokers. Participants will be stratified by lung cancer risk based on airway obstruction, prior history of completely resected stage I non-small cell lung cancer, and the histopathology of bronchial biopsies. They will be randomized 2:1 to drug vs. placebo. A surrogate marker of lung cancer, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previously and currently investigated by us and others (MCM2, hnRNP, apoptosis, cytokine response profiles, (epi) genetic alterations, morphology) will be explored as surrogate trial endpoints. Exisulind will be given orally at a dose of 500 mg daily for 6 months. With 93 evaluable participants randomized to exisulind, the study will have 80% power to detect a 50% or greater decrease in the mean Ki-67 labelling index as a result of treatment. Since we anticipate a 25% attrition rate, we are planning to enroll a total of 186 subjects over 4 years. Given the number of eligible subjects at our institution that already participate in early detection trials, we are confident that the goal of this proposed study can be achieved during the 5-years of funding. The data generated by these investigations will be important for future decisions on large-scale chemoprevention trials using disease incidence and mortality as endpoints.