Lung Cancer Chemoprevention with Enzastaurin

在美国，肺癌占所有癌症相关死亡的近三分之一，治愈率 保持低。因此，需要开发可以预防处于风险中的个体的疾病的化合物。 吸烟、阻塞性肺疾病和年龄是压倒性的危险因素。的人员 已经戒烟的人一生中患肺癌的风险增加， 吸烟的香烟。前吸烟者是化学预防特别有吸引力的目标人群 药物治疗。一些化合物已经过测试，但迄今为止还没有结果 肺癌发病率的下降。事实上，两个大规模的化学预防试验， β-胡萝卜素在当前和以前的吸烟者中，导致肺结核的发病率和死亡率增加， 癌对这些研究和其他相关已发表报告的亚组分析表明， 并且对化学预防剂的生物反应在主动吸烟者和前吸烟者之间不同。在全国范围内， 肺癌化学预防的重点是抑制炎症反应途径和生长 因子信号通路和使用中间生物标志物作为主要试验终点。一种新型药剂， 具有抗增殖、促凋亡和最小毒性作用的是恩扎鲁因（LY 317615）。它是一种口服蛋白质 激酶C（PKC）抑制剂，目前正在II期和III期试验中进行临床疗效测试， 各种恶性肿瘤为了测试这种药物在预防肺癌方面的临床效用，我们将进行一项 在既往吸烟者中进行的双盲、安慰剂对照、随机化IIb期试验。肺的替代标志物 癌症风险，增殖标志物Ki-67，将被用作主要终点。以前的其他标记 目前，我们和其他人正在调查，特别是DMA复制原点许可的组成部分 复杂，也将作为替代试验终点进行探索。这些调查产生的数据将 不仅确定了恩扎鲁肽作为肺癌化学预防剂的功效， 为今后的研究提供重要的分析线索。

Lung cancer is responsible for nearly one-third of all cancer-related death in the U.S., and the cure rates remain low. Thus, there is a need to develop compounds that can prevent the disease in individuals at risk. Cigarette smoking, obstructive pulmonary disease, and age are the overwhelming risk factors. Persons that have quit smoking remain at an increased risk for lung cancer for lifetime that is proportional to the amount of cigarettes smoked. Former smokers are a particularly attractive target population for chemoprevention with pharmacological agents. 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, which evaluated beta-carotene in current and former smokers, resulted in an increase of incidence and mortality from lung cancer. Subgroup analyses of these studies and other related published reports suggest that the clinical and biologic responses to chemopreventive agents differ between active and former smokers. Nationally, the focus of lung cancer chemoprevention is on inhibitors of inflammatory response pathways and growth factor signaling pathways and the use of intermediate biomarkers as primary trial endpoints. A novel agent with antiproliferative, proapoptotic, and minimal toxic effects is enzastaurin (LY317615). It is an oral protein kinase C (PKC) inhibitor currently undergoing clinical efficacy testing in phase II and III trials in patients with a variety of malignancies. To test the clinical utility of this agent in lung cancer prevention, we will conduct a double-blind, placebo-controlled, randomized phase lib trial in former smokers. A surrogate marker of lung cancer risk, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previously and currently investigated by us and others, in particular components of the DMA replication origin licensing complex, will also be explored as surrogate trial endpoints. The data generated by these investigations will not only determine the efficacy of enzastaurin as a chemopreventive agent for lung cancer, but also provide important analytical leads for future studies.