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%)。迫切需要开发一种化合物，这种化合物可以在有吸烟史和其他与肺癌风险增加相关的因素的个人中预防这种疾病。已经对一些化合物进行了测试，但到目前为止，试验并未导致肺癌发病率的下降。事实上，两项大规模的化学预防试验评估了活跃吸烟者和戒烟者中的β-胡萝卜素，结果导致肺癌发病率和死亡率的增加。近年来，肺癌化学预防的研究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。一类新的诱导细胞凋亡的药物已经被开发出来。Exisulind(Aptosyn)是这类药物中的第一个，它通过减少人类腺瘤性息肉的大小，在结直肠癌的化学预防方面显示出希望。在动物研究中，这种药物可以减少致癌物诱发的肺癌。为了测试这种药物在肺癌预防中的临床有效性，我们建议对既往吸烟者进行双盲、安慰剂对照、随机临床疗效试验。参与者将根据呼吸道阻塞、既往完全切除的I期非小细胞肺癌病史和支气管镜活检的组织病理学情况对患者进行肺癌风险分层。他们将被随机分为药物和安慰剂两组。肺癌的替代标记物，增殖标记物Ki-67将被用作主要终点。我们和其他人以前和目前研究的其他标记物(MCM2、hnRNP、细胞凋亡、细胞因子反应谱、(EPI)遗传改变、形态)将被探索作为替代试验的终点。Exisulind将以每天500毫克的剂量口服，持续6个月。93名可评估的参与者随机进入Exisulind，这项研究将有80%的力量检测到治疗后Ki-67平均标记指数下降50%或更多。由于我们预计流失率为25%，我们计划在4年内招收186名学生。考虑到我们机构中已经参与早期检测试验的合格受试者的数量，我们有信心在5年的资助期间能够实现这项拟议研究的目标。这些调查所产生的数据对于以发病率和死亡率为终点的大规模化学预防试验的未来决策将是重要的。

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.