Nutrition and Anabolic Interventions in Cancer Cachexia

癌症恶病质的营养和合成代谢干预

• 批准号: 8020013
• 负责人: Melinda Sheffield-Moore
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 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/8020013
• 关键词: Actins; Actomyosin; Address; Affect; Aging; Amino Acids; Anabolism; Appetite Depressants; 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; Complement Factor B; Complex; Data; Double-Blind Method; Eating; Endocrinology; Equilibrium; Essential Amino Acids; Exhibits; Functional disorder; Gene Expression; Goals; Health; 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; 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

DESCRIPTION (provided by applicant): 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-1 (TNF-1) 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 anti-anorectic and anti-cachexic effects of leucine-enhanced essential amino acids (L-EAA) supplemented concomitantly with testosterone's anabolic and anti-catabolic 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. PUBLIC HEALTH 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.

描述(申请人提供)：癌症恶病质严重消耗骨骼肌群，导致身体功能受损和生活质量下降。在临床领域，营养不良和恶病质是同义词。然而，恶病质比单纯的卡路里缺乏要复杂得多，因为改善营养状况并不能扭转或防止肌肉萎缩。我们的初步数据显示，癌症患者骨骼肌蛋白对氨基酸合成代谢刺激的反应受损。 我们认为肿瘤和体液分解代谢因子引起的持续性、全身性和局限性的骨骼肌炎症改变了癌症患者骨骼肌蛋白质平衡的失调。具体地说，这些因素通过影响合成和分解来改变肌肉蛋白质平衡的调节。合成受到影响是因为分解代谢因子降低了血浆中关键支链氨基酸的浓度，如亮氨酸，从而抑制了营养来源的合成代谢的刺激。分解受到影响是因为分解代谢因子如肿瘤坏死因子-1(TNF-1)促进核因子-B(核因子-B)，而核因子-B又通过泛素-蛋白酶体系统激活肌肉蛋白分解。我们的数据表明，癌症患者的骨骼肌表现出核因子-B的激活增加和炎症负担的增加。最近，我们发现3个月的睾酮治疗下调了泛素和E3泛素连接酶MuRF1和MAFbx/Atrogin-1的基因表达，并在肌动球蛋白破坏的初始步骤阻止了一种新的14-kD肌动蛋白片段的切割。我们的一般假设是，亮氨酸增强型必需氨基酸(L-EAA)的抗厌食和抗恶病质作用与睾酮的合成代谢和抗分解代谢特性相结合，将分别通过增加对蛋白质合成的刺激和通过抑制肌肉蛋白分解的激活来增加晚期(IIB期、IIIA期和IIIB期)或复发宫颈癌患者的瘦肉量。 我们将进行一项随机、双盲、安慰剂对照干预研究，旨在临床和机械地评估新的营养(L-EAA)和药物(睾酮)疗法，旨在结合标准护理(SOC)治疗预防癌症相关肌肉萎缩或使其正常化。我们将确定这一新的治疗方法对晚期或复发宫颈癌患者的以下预后指标的有效性：1)瘦体重和肌肉力量，2)肌肉蛋白质周转，3)骨骼肌萎缩的炎性生物标志物和信号通路。公共卫生叙事。宫颈癌是女性中第二常见的癌症，全球每年新增47万例。这项研究将测试营养和激素是否可以防止与癌症相关的肌肉损失。我们的研究很重要，因为在所有癌症死亡中，肌肉极度萎缩至少占20%。这项研究的结果可能会导致更好的方法来预防癌症相关的体重减轻，并改善那些受宫颈癌影响的人的生活质量和生存率。