Chemoprevention of Lung Cancer with Mitochondria-Targeted Honokiol

项目摘要： 非小细胞肺癌是最常见的肺癌，占所有肺癌的85% 在美国的案件。吸烟是这种疾病的主要原因， 仍然处于较高的风险之中。约40%的NSCLC是腺癌（LUAD）。2005年LUAD病例数 吸烟者人数预计将上升。在高危人群中LUAD发展的化学预防， 戒烟是降低NSCLC死亡率的重要策略。此外，LUAD转移到 大脑是导致死亡的主要原因之一。因此，发现新的战略，以防止原发性和 转移性LUAD至关重要。因为接受预防性治疗的患者没有明显的 对于一种疾病，这种治疗不仅必须有效，而且必须具有非常低的副作用风险。Honokkalan（HNK）， 一种天然化合物，存在于黄柏提取物中，具有良好的安全性， 在动物模型中预防几种癌症的发展。我们最近证明了 HNK在小鼠肺肿瘤发生的化学预防中的功效。HNK的作用机理分析 表明其作用主要是通过诱导凋亡介导的， 机制这为将HNK与靶向剂缀合提供了支持性的基本原理，所述靶向剂驱动HNK进入靶向剂。 线粒体，以显着提高其化学预防功效。初步数据显示， 靶向HNK（Mito-HNK）也是LUAD脑的显著更有效的化学预防剂 转移（疾病的常见临床特征）比HNK。我们假设Mito-HNK是一部小说， LUAD进展和转移的有效化学预防剂，主要通过新的 线粒体机制这一假设将在三个具体目标中得到检验。目标1将评估 Mito-HNK的体外化学预防潜力和作用机制。目标2将决定 Mito-HNK对A/J小鼠中肺肿瘤进展的化学预防功效。目标3将决定 Mito-HNK对LUAD脑转移瘤的化学预防作用。我们会用最先进的小动物 成像技术，以监测原发性肿瘤的生长（磁共振成像）和植入 转移性细胞以及用于体内监测癌细胞变化的创新方法 生物能量学和细胞氧化剂产生（生物发光成像）。这将使精确和准确的 监测Mito-HNK在肿瘤发生的不同阶段的功效。开发一种 因此，一种新的、有效的LUAD化学预防剂将是非常重要的。由此产生的知识 该提案可用于指导未来的临床试验，并可指导开发一种完全 用于LUAD化学预防的新类别的药剂。

Project Summary: Non-small-cell lung cancers (NSCLCs) are the most common lung cancers, accounting for 85% of all lung cancer cases in the United States. Cigarette smoking is the predominant cause of this disease and former smokers remain at elevated risk. About 40% of NSCLCs are adenocarcinomas (LUAD). The number of LUAD cases in former smokers is expected to rise. Chemoprevention of LUAD development in at-risk populations such as former smokers is an important strategy to reduce NSCLCs mortality. Furthermore, metastasis of LUAD to the brain is one of the leading causes of mortality. Thus, discovering new strategies to prevent primary and metastatic LUAD is critically important. Because patients who will receive preventive treatment do not have overt disease, such treatments must not only be effective but also have a very low risk of side effects. Honokiol (HNK), a natural compound present in magnolia bark extracts, has a favorable safety profile and has been shown to prevent the development of several types of cancer in animal models. We have recently demonstrated potent efficacy of HNK in the chemoprevention of lung tumorigenesis in mice. Analysis of HNK’s mechanism of action suggests that its effect is primarily mediated by inducing apoptosis through a mitochondria-dependent mechanism. This provides a supportive rationale for conjugating HNK to a targeting agent that drives it into mitochondria in order to dramatically increase its chemopreventive efficacy. Preliminary data demonstrate that mitochondria-targeted HNK (Mito-HNK) is also a significantly more potent chemopreventive agent of LUAD brain metastasis (a common clinical feature of the disease) than HNK. We hypothesize that Mito-HNK is a novel, potent chemopreventive agent of LUAD progression and metastasis and acts primarily through novel mitochondrial mechanisms. This hypothesis will be tested in three specific aims. Aim 1 will evaluate the chemopreventive potential and mechanisms of action of Mito-HNK in vitro. Aim 2 will determine the chemopreventive efficacy of Mito-HNK on lung tumor progression in A/J mice. Aim 3 will determine the chemopreventive efficacy of Mito-HNK on LUAD brain metastasis. We will use state-of-the-art small animal imaging technology to monitor the growth of primary tumors (magnetic resonance imaging) and engraftment of metastatic cells as well as innovative approaches for in vivo monitoring of the changes in cancer cell bioenergetics and cellular oxidant production (bioluminescent imaging). This will enable precise and accurate monitoring of the efficacy of Mito-HNK in distinct stages of tumorigenesis. The clinical impact of developing a novel, potent agent for LUAD chemoprevention will be highly significant. The knowledge generated from this proposal could be used to direct the course of future clinical trials and may guide the development of an entirely new class of agents for LUAD chemoprevention.