P4 - Lung Cancer Chemoprevention with Enzastaurin

P4 - 使用 Enzastaurin 进行肺癌化学预防

• 批准号: 8118131
• 负责人: GEROLD BEPLER
• 金额: $ 37.45万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118131
• 关键词: Accounting; Adult; Age; Apoptosis; Beta Carotene; Biological Markers; Biopsy; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Chest; Chromatin; Cigarette; Clinical; Clinical Practice Guideline; Complex; Cytokine Signaling; DNA replication origin; Data; Development; Disease; Double-Blind Method; Dysplasia; Environmental Exposure; Epithelial Cells; FDA approved; Future; G1 Phase; Genetic; Growth Factor; Histopathology; Incidence; Individual; Inflammatory; Inflammatory Response Pathway; Intervention; Investigation; LY317615; Label; Licensing; Lobar bronchus structure; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metaplasia; Morphology; Non-Small-Cell Lung Carcinoma; Oral; Participant; Patients; Persons; Phase; Phase II/III Trial; Placebo Control; Population; Proliferation Marker; Protein Kinase C; Protein Kinase C Inhibitor; Publishing; Randomized; Recording of previous events; Replication Origin; Reporting; Resected; Risk; Risk Factors; Signal Pathway; Smoke; Smoker; Staging; Subgroup; Surrogate Endpoint; Surrogate Markers; Target Populations; Testing; Therapeutic Intervention; Toxic effect; United States; airway obstruction; base; cancer chemoprevention; cancer risk; cancer therapy; carcinogenesis; cigarette smoking; citrate carrier; clinical efficacy; efficacy testing; evidence base; indexing; inhibitor/antagonist; lung cancer prevention; member; mortality; novel; prevent; randomized placebo controlled trial; response; smoking cessation; systemic intervention; theories

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.

肺癌造成了美国所有与癌症有关的死亡的近三分之一，治愈率和治愈率 保持低。因此，有必要开发可以防止患有危险的个体疾病的化合物。 吸烟，阻塞性肺部疾病和年龄是压倒性的危险因素。那个人 戒烟是否仍处于肺癌终生的风险增加，这与数量成正比 抽烟。前吸烟者是化学预防的特别有吸引力的目标人群 与药理剂。已经测试了许多化合物，但迄今为止的试验尚未进行 肺癌发病率的降低。实际上，两项评估的大规模化学预防试验 当前和前吸烟者中的β-胡萝卜素导致肺发病率和死亡率升高 癌症。这些研究的亚组分析和其他相关已发表的报告表明临床 活性和以前的吸烟者之间对化学预防剂的生物反应不同。在全国范围内 肺癌化学预防的重点是炎症反应途径和生长的抑制剂 因子信号通路和使用中间生物标志物作为主要试验终点的使用。一个新颖的代理 抗增生性，促凋亡和最小毒性作用是enzastaurin（Ly317615）。这是一种口服蛋白 激酶C（PKC）抑制剂目前在II期和III期试验中接受临床疗效测试的患者 各种恶性肿瘤。为了测试该药物在预防肺癌中的临床实用性，我们将进行一次 以前吸烟者的双盲，安慰剂对照，随机相位的自由植物试验。肺的替代标记 癌症风险（扩散标记KI-67）将被用作主要终点。以前的其他标记 目前由我们和其他人进行调查，特别是DMA复制起源许可的组成部分 复杂的，也将作为替代试验终点探索。这些调查产生的数据将 不仅确定Enzastaurin作为肺癌化学预防剂的功效，而且还提供 重要的分析铅用于未来的研究。