Development of Dietary Quercetin to Treat Muscle Wasting Disorders

项目总结：恶病质，体重的无意损失，是常见的慢性疾病和相关的治疗。恶病质与身体功能下降、治疗耐受性降低和死亡率增加有关。此外，与非恶病质患者相比，恶病质诊断与住院时间加倍和4，000美元/例的额外费用一致。据报道，化疗治疗后会出现恶病质，包括肌肉质量损失和疲劳，导致生活质量下降。此外，伴有恶病质的瘦体重损失损害化疗治疗耐受性，并可加剧功能减退，导致功能依赖性和累积的医疗保健成本。单一和联合化疗药物，如5氟尿嘧啶（5 FU）和FOLFIRINOX已被证明直接破坏荷瘤小鼠的骨骼肌质量和功能。此外，在动物和人类中给予5 FU和FOLFIRINOX诱导体重减轻，与骨骼肌质量减轻和线粒体功能破坏相关，代表研究恶病质的理想模型。目前，尽管我们对肌肉萎缩机制的理解有所提高，但仍没有批准用于恶病质的治疗方法。槲皮素是一种存在于各种水果和蔬菜中的天然多酚，因其抗炎特性和增加线粒体生物合成的能力而被公认。我们已经收集了令人信服的数据，支持进一步研究槲皮素作为预防/治疗恶病质的药剂：1）我们报道了槲皮素可以减少癌症诱导的恶病质; 2）我们表明槲皮素可以减少与化疗相关的身体疲劳; 3）我们报道了槲皮素可以通过增加线粒体生物合成来增加身体表现; 4）我们报道了槲皮素可以通过增加线粒体生物合成来增加身体表现。4）我们发现槲皮素可以减少许多疾病模型中的炎症。然而，槲皮素尚未被开发为预防或治疗恶病质的药剂。我们的长期目标是将这种膳食化合物作为预防/治疗恶病质的创新药物推向人类临床试验。在这个I期SBIR项目中，我们将严格测试膳食槲皮素将改善癌症和化疗诱导的恶病质，从而改善治疗结果的假设。提出了三个具体目标：1）评价槲皮素对改善癌症和化疗诱导的恶病质的作用，2）建立槲皮素的有效血浆和肌肉水平以及给药间隔，以及3）在小鼠中进行槲皮素的亚慢性口服毒性筛选。我们提出的I期SBIR研究的成功将进一步开发槲皮素作为预防/治疗恶病质的新药物。后续II期SBIR计划将在这些初步研究的基础上扩展：1）使用其他恶病质模型完成槲皮素的疗效研究; 2）完成小鼠的高级药物毒理学研究。第二阶段的总体目标是将AcePre LLC定位为FDA预研究新药包。

PROJECT SUMMARY: Cachexia, the unintentional loss of body weight, is prevalent in chronic diseases and associated treatments. Cachexia is associated with reduced physical function, decreased tolerance for treatment, and increased mortality. Moreover, a cachexia diagnosis is consistent with a doubling in duration of hospital stay and an additional cost of $4,000/case compared to non-cachectic patients. Cachexia has been reported following chemotherapy treatment including muscle mass loss and fatigue which contribute to reduced quality of life. Furthermore, the loss of lean mass with cachexia impairs chemotherapy treatment tolerance and can exacerbate functional decrements leading to functional dependencies and accrued health care cost. Single and combined chemotherapeutic agents such as 5 fluorouracil (5FU) and FOLFIRINOX have been shown to directly disrupt skeletal muscle mass and function in tumor-bearing mice. Additionally, 5FU and FOLFIRINOX administration in animals and humans induces body weight loss associated with skeletal muscle mass loss and disrupted mitochondrial function, representing as an ideal model to study cachexia. Currently, there are no approved therapies for cachexia despite the improvements in our understanding of the mechanisms underlying muscle wasting. Quercetin, a natural polyphenol found in various fruits and vegetables, has been recognized for its anti-inflammatory properties and its ability to increase mitochondrial biogenesis. We have collected convincing data that support further investigation of Quercetin as an agent to prevent/treat cachexia: 1) we reported that Quercetin can reduce cancer-induced cachexia; 2) we showed that Quercetin can reduce the physical fatigue that is associated with chemotherapy; 3) we reported that Quercetin can increase physical performance by increasing mitochondrial biogenesis; and 4) we showed that Quercetin can reduce inflammation in a number of disease models. However, Quercetin has not yet been developed as an agent to prevent or treat cachexia. Our long-term goal is to move this dietary compound towards human clinical trials as an innovative agent to prevent/treat cachexia. In this Phase I SBIR project we will rigorously test the hypothesis that dietary Quercetin will ameliorate the cancer and chemotherapy-induced cachexia and thereby result in improved therapeutic outcomes. Three specific aims are proposed: 1) evaluate Quercetin’s effects on ameliorating cancer and chemotherapy-induced cachexia, 2) establish the effective plasma and muscle levels and dosing interval for Quercetin, and 3) perform a subchronic oral toxicity screening of Quercetin in mice. The success of our proposed phase I SBIR study will further the development of Quercetin as a new agent to prevent/treat cachexia. A follow-up Phase II SBIR program will expand on these initial studies to: 1) complete efficacy studies of Quercetin using additional models of cachexia; and 2) complete advanced pharmaceutical toxicology studies in mice. The overall goal of Phase II will be to position AcePre LLC for an FDA Pre-Investigational New Drug package.