Long-acting ghrelin for the treatment of cancer cachexia

项目摘要 恶病质是一种复杂的综合征，其特征是不自主的体重减轻和骨骼肌萎缩， 导致疲劳、虚弱和食欲不振，增加热量消耗无法逆转。更 一半以上的癌症患者会发展成恶病质，并且恶病质是所有癌症死亡的20%以上的原因。 与恶病质相关的许多并发症包括对药物治疗的反应受损， 感染的机会增加，预后不良，生活质量下降。目前，没有FDA- 癌症恶病质的批准治疗，但激素ghrelin最近出现作为一种分子， 很有潜力。在动物和人类身上的几项研究表明，ghrelin增加食物摄入， 刺激生长激素的释放，增加肌肉质量，减少炎症标志物。 然而，由于以下几个原因，生长激素释放肽作为治疗的使用受到限制：1）生长激素释放肽必须给药2-3次 由于其固有的30分钟的短半衰期，每天观察功效; 2）将生长素释放肽脱酰化为无活性形式 在少于5分钟内发生;和3）胃饥饿素目前静脉内给药以观察治疗效果。的 在SBIR第一阶段完成的研究解决了这些问题中的每一个，产生了长效生长激素释放肽衍生物 可以每隔一天皮下给药一次，以逆转恶病质在大鼠中的作用。 Yoshida大鼠模型在第二阶段申请中提出的研究将调查我们长期的能力， 在另外两个模型中，作用于生长激素释放肽以改善恶病质。用于长效的cGMP生产的方法 胃促生长素将被放置到位。我们将使用以下方法进行IND使能GLP毒性和免疫原性研究： cGMP材料。在开始人体试验之前，需要进行这些研究。一旦发育完全，这一漫长的- 有效的生长素释放肽衍生物将提供一种患者友好的恶病质治疗， 癌症患者以及其他慢性疾病患者的预后和生活质量 充血性心力衰竭（CHF）和慢性阻塞性肺病（COPD）。

Project Summary Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More than half of all cancer patients develop cachexia and it is responsible for more than 20% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cancer cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake, stimulates the release of growth hormone, increases muscle mass, and reduces markers of inflammation. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 30 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies completed during SBIR Phase I address each of these issues, resulting a long-acting ghrelin derivative that could be dosed subcutaneously once every other day in rats to reverse the effects of cachexia in the Yoshida rat model. The studies proposed in this Phase II application will investigate the ability of our long- acting ghrelin to ameliorate cachexia in two additional models. Methods for cGMP production of the long-acting ghrelin will be put in place. We will perform IND-enabling GLP toxicity and immunogenicity studies using the cGMP material. These studies are needed prior to beginning human trials. Once fully developed, this long- acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patients with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD).