The Role of Ghrelin in Cancer Cachexia

描述（由申请人提供）： 每年，美国有超过150万人被诊断患有癌症。恶病质，定义为非自愿体重减轻> 5%，存在于高达80%的这些患者中，并且是食物摄入和能量消耗（EE）之间不平衡的结果。恶病质导致功能表现、生活质量和生存率下降。然而，缺乏对这种情况的治疗。在非癌症模型中，激素ghrelin或其模拟物（GHS）的施用增加能量摄入并降低能量消耗。这会导致瘦体重（LBM）和脂肪量增加。然而，它们在癌症恶病质中的作用尚未确定。本研究的长期目标是确定ghrelin模拟物影响能量摄入和能量消耗的程度，以及这些变化对恶病质癌症患者体重，身体成分，蛋白质积累和功能表现的影响。我们的假设是，在癌症诱导的恶病质的情况下，与安慰剂相比，生长激素释放肽模拟物（GHS）将：a）增加食欲和食物摄入，B）增加体重、LBM和蛋白质质量，并防止脂肪损失，c）减少静息EE和d）增加肌肉力量和功能表现。具体目标是在癌症诱导的恶病质退伍军人中确定GHS对以下方面的影响：1）食欲和食物摄入，2）体重和身体组成，3）静息能量消耗和4）功能表现。此外，我们有一个探索性的目的，建立GHS对循环TNF-1和IL-6水平在这种情况下的影响。假设GHS会减少这些标记物。研究设计和方法：在这项双盲、安慰剂对照试验中，90名患有非小细胞肺癌和恶病质的受试者将被随机分配至：1）安慰剂组或2）GHS组，持续12周。将在第4、8和12周评估安全性和疗效，并比较组间较基线的变化。通过视觉模拟量表评估食欲，通过食物日记评估摄食量。瘦体重将通过全身钾测量进行评估;蛋白质含量通过即时3-活化系统进行评估，脂肪量通过DEXA进行评估。静息能量消耗将通过间接量热法测量。将通过问卷调查和测量肌肉力量、体力活动水平、爬楼梯能力和6分钟步行试验的变化来评估功能表现。将通过ELISA测量IL-6和TNF-1。与VA使命的相关性：本提案将提高我们对影响癌症患者的症状的理解。总的来说，这些结果将建立饥饿素模拟物在癌症恶病质中的作用，并使我们深入了解其作用机制。这将改善生活质量，并可能为治疗这些症状开辟新的途径。功能性能的改善预计将使患者能够更长时间地留在家中，减少住院需求并降低医疗保健成本。 公共卫生相关性： 癌症及其并发症，包括恶病质（非自愿体重减轻）和厌食症（食欲不振）是我们退伍军人中非常常见的问题。我们建议测试一种名为anamorelin的新型药物对患有癌症恶病质和厌食症的退伍军人的影响。这一建议将对他们的生活质量产生直接影响，并将为治疗这些目前尚无有效治疗方法的症状开辟新途径。这些症状的改善也将使患者能够更长时间地呆在家里，减少住院治疗的需要并降低医疗保健费用。与恶病质相关的其他疾病，如心力衰竭或慢性肺病，在我们的退伍军人中非常常见，可能会从这项提议带来的知识中受益，因为拟议实验产生的结果将为这些条件下的未来试验奠定基础。

DESCRIPTION (provided by applicant): Every year, over 1.5 million individuals in the US are diagnosed with cancer. Cachexia, defined as an involuntary weight loss >5%, is present in up to 80% of these patients and is the result of an imbalance between food intake and energy expenditure (EE). Cachexia contributes to a decrease in functional performance, quality of life and survival. However, treatments for this condition are lacking. In non-cancer models, administration of the hormone ghrelin or its mimetics (GHS) increases energy intake and decreases energy expenditure. This leads to an increase in lean body mass (LBM) and fat mass. However, their role in cancer cachexia has not been established. The long-term objective of this research is to determine the extent to which ghrelin mimetics will affect energy intake and energy expenditure, and the effect that these changes will have on body weight, body composition, protein accretion and functional performance in cancer patients with cachexia. Our hypotheses are that, in the setting of cancer-induced cachexia and compared to placebo, ghrelin mimetics (GHS) will: a) increase appetite and food intake, b) increase body weight, LBM and protein mass, and prevent fat loss, c) decrease resting EE and d) increase muscle strength and functional performance. The specific aims are to establish in veterans with cancer-induced cachexia the effects of GHS on: 1) appetite and food intake, 2) body weight and body composition, 3) resting energy expenditure and 4) functional performance. In addition, we have an exploratory aim of establishing the effect of GHS on circulating TNF-1 and IL-6 levels in this setting. The hypothesis is that GHS will decrease these markers. Research Design and Methods: In this double-blind, placebo-controlled trial, 90 subjects with non-small cell lung cancer and cachexia will be randomized to: 1) placebo or 2) GHS for 12 weeks. Safety and efficacy will be assessed at 4, 8 and 12 weeks and comparisons will be made for changes from baseline between groups. Appetite will be assessed by a visual analogue scale and food intake by a food diary. Lean body mass will be assessed by total body potassium measurement; protein content by prompt 3-activation system and fat mass by DEXA. Resting energy expenditure will be measured by indirect calorimetry. Functional performance will be assessed by questionnaires and by measuring changes in muscle strength, physical activity levels, stair climbing power and the 6-minute walk test. IL-6 and TNF-1 will be measured by ELISA. Relevance to the VA Mission: The present proposal will improve our understanding of symptoms that affect cancer patients. Collectively, these outcomes will establish the role of ghrelin mimetics in cancer cachexia and give us an insight into their mechanisms of action. This will improve quality of life and may open new avenues for the treatment of these symptoms. An improvement in functional performance is expected to allow patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. PUBLIC HEALTH RELEVANCE: Cancer and its complications including cachexia (involuntary weight loss) and anorexia (poor appetite) are very common problems in our veterans. We propose to test the effects of a novel agent called anamorelin on veterans with cancer cachexia and anorexia. This proposal will have a direct impact on their quality of life and will open new avenues for the treatment of these symptoms for which there are no effective treatments at this point. An improvement in these symptoms also will allow patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. Other conditions associated with cachexia such as heart failure or chronic lung disease are very common in our veterans and may benefit from the knowledge that this proposal will bring because the results generated by the proposed experiments will set the bases for future trials in these conditions.