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Nutrition and Anabolic Interventions in Cancer Cachexia

癌症恶病质的营养和合成代谢干预

基本信息

批准号：
8325963
负责人：
Melinda Sheffield-Moore
金额：
$ 26.82万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-18 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8325963
关键词：
Actins Actomyosin Address Affect Aging Amino Acids Anabolism Appetite Stimulants Atrophic Bed rest Biological Markers Body Weight Body Weight decreased Branched-Chain Amino Acids Cachexia Cancer Patient Catabolic Process Cause of Death Cervix carcinoma Cessation of life Clinical Complex Data Double-Blind Method Eating Endocrinology Equilibrium Essential Amino Acids Exhibits Functional disorder Gene Expression Goals Healthy People 2010 Hormonal Hormones Impairment Inflammation Inflammatory Injection of therapeutic agent Intake Intervention Intervention Studies Kinetics Lead Leucine Malignant Neoplasms Malignant neoplasm of cervix uteri Malnutrition Muscle Muscle Proteins Muscular Atrophy Nuclear Nutritional Nutritional status Outcome Measure Pathway interactions Patients Physical Function Placebo Control Placebos Plasma Population Heterogeneity Prevention Research Process Property Protein Biosynthesis Proteins Proteolysis Qualifying Quality of life Randomized Recurrence Regulation Research Research Design Signal Pathway Skeletal Muscle Staging Stimulus Syndrome System TNF gene Testing Testosterone Trauma Tumor Necrosis Factor-alpha Ubiquitin Woman Writing abstracting cancer prevention cancer therapy clinically significant cytokine disability experience hormone therapy improved malignant muscle neoplasm multicatalytic endopeptidase complex muscle form muscle strength novel novel therapeutic intervention nutrition prevent protein degradation response standard of care success transcription factor translational study ubiquitin-protein ligase wasting

项目摘要

Project Summary/Abstract Cancer cachexia severely depletes skeletal muscle mass leading to impairments in physical function and a diminished quality of life. In the clinical realm, malnutrition and cachexia are synonymous. However, cachexia is more complex than mere caloric deficiency, since improving nutritional status does not reverse or prevent muscle wasting. Our preliminary data show that the response of skeletal muscle protein to the anabolic stimulus of amino acids is impaired in cancer patients. We propose that the dysregulation of skeletal muscle protein balance in cancer patients is altered by persistent systemic and localized skeletal muscle inflammation derived from tumoral and humoral catabolic factors. Specifically, these factors alter the regulation of muscle protein balance by affecting both synthesis and breakdown. Synthesis is affected because catabolic factors diminish the plasma concentrations of key branched-chain amino acids such as leucine, thereby suppressing the stimulus for nutrition-derived anabolism. Breakdown is affected because catabolic factors such as tumor necrosis factor-? (TNF-?) enhance nuclear factor-?B (NF-?B), which in turn activates muscle proteolysis via the ubiquitin-proteasome system. Our data demonstrate that skeletal muscle in cancer patients exhibits increased activation of NF-?B and enhanced inflammatory burden. More recently, we found that 3 months of testosterone therapy downregulates ubiquitin and the E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1 gene expression along with blocking cleavage of a novel 14-kD actin fragment in the initial step of actomyosin destruction. Our general hypothesis is that the antianorectic and anticachectic effects of leucine-enhanced essential amino acids (L-EAA) supplemented concomitantly with testosterone's anabolic and anticatabolic properties will enhance lean muscle mass in patients with advanced (stages IIB, IIIA and IIIB) or recurrent cervical carcinoma by increasing the stimulus for protein synthesis, and by inhibiting the activation of muscle proteolysis, respectively. We will conduct a randomized, double-blind, placebo-controlled intervention study designed to clinically and mechanistically assess novel nutritional (L-EAA) and pharmacologic (testosterone) therapies aimed at preventing or normalizing cancer-related muscle wasting in conjunction with standard of care (SOC) treatment. We will determine the efficacy of this novel therapeutic approach on the following outcome measures in patients with advanced or recurrent cervical carcinoma: 1) lean body mass and muscle strength, 2) muscle protein turnover, and 3) inflammatory biomarkers and signaling pathways of atrophy in skeletal muscle. Project Narrative Cervical cancer is the second most prevalent cancer in women, with 470,000 new cases occurring globally each year. This study will test whether nutrition and hormones can prevent cancer-related muscle loss. Our study is important because extreme muscle loss is responsible for at least 20% of all cancer deaths. Results from this study may lead to better ways of preventing cancer-related weight loss, and improve the quality of life and survival of those affected by cervical cancer.

项目总结/文摘