Development of Dietary Quercetin to Treat Muscle Wasting Disorders

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.PROJECT NARRATIVE Cachexia, the unintentional loss of body weight, is associated with reduced physical function, decreased tolerance for treatment, and increased mortality. 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 – factors that have been associated with driving cachexia. We will perform dose-escalating studies to establish the dose-range by which Quercetin can counteract chemotherapy-induced cachexia and associated adverse physiological outcomes, which will move this dietary compound towards human clinical trials as an innovative agent to prevent/treat cachexia.