(PQB-3) Roles of skeletal muscle mass in chemotherapy-associated cachexia

(PQB-3) 骨骼肌质量在化疗相关恶病质中的作用

• 批准号: 8791734
• 负责人: Andrea Bonetto
• 金额: $ 20.36万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791734
• 关键词: ACVR2B gene; Accounting; Adipose tissue; Adverse effects; Affect; Anorexia; Antineoplastic Agents; Atrophic; Attention; Automobile Driving; Biology; Body Composition; Body Weight decreased; Cachexia; Cancer Etiology; Cancer Patient; Cell Culture Techniques; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Oncology; Colon; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Diagnosis; Diarrhea; Dose; Drug toxicity; Experimental Models; Family; Fatigue; Fatty acid glycerol esters; Fiber; Genes; Goals; Growth; Growth Factor; Homeostasis; Human; In Vitro; Inflammatory; Inflammatory Response; Life; Ligands; Light; Malignant Neoplasms; Mediator of activation protein; Modification; Molecular; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Nausea; Pathway interactions; Patients; Peptides; Performance Status; Pharmaceutical Preparations; Process; Production; Publishing; Quality of life; Regimen; Reporting; Research Proposals; Role; Safety; Serum; Skeletal Muscle; Symptoms; Syndrome; Time; Toxic effect; Work; cancer therapy; chemotherapy; cytokine; cytotoxic; drug efficacy; gemcitabine; grasp; host neoplasm interaction; improved; in vitro testing; in vivo; in vivo Model; irinotecan; mortality; muscle form; muscle hypertrophy; muscle strength; myostatin; nitrogen balance; novel; public health relevance; response; synthetic peptide; transcriptomics; tumor; tumor growth; wasting

DESCRIPTION (provided by applicant): The primary goal of this research proposal is to understand the impact of chemotherapy on muscle mass and function, and to investigate whether muscle hypertrophy can protect against cancer cachexia and improve drug efficacy and patients' survival. It has been postulated that chemotherapy, among several other side effects, is also responsible for the development of cachexia. Cachexia, i.e. loss of body weight, muscle and fat mass, has currently no cure. The molecular mechanisms responsible for the development of this syndrome have been studied for some time, however little is known about the effects of various cancer treatments on cancer cachexia. On this line, it has been reported that several anticancer drugs can cause direct host cell modification as well as induce a negative nitrogen balance. However, the mechanism(s) regulating these processes deserve further attention. Our preliminary data and others' published findings support the idea that chemotherapy might promote muscle depletion. Indeed, chemotherapeutics such as cisplatin, irinotecan and gemcitabine, widely used in the treatment of different kinds of cancer, caused dose-dependent muscle fiber wasting in vitro and in vivo. Similarly, severe body weight loss and muscle atrophy were observed in mice bearing the Colon-26 and HCT- 116 colorectal cancers. Cancer patients affected by muscle depletion were more susceptible to severe chemotherapy-associated toxicity and showed reduced survival unlike subjects with larger muscle mass. Others and we showed that improving muscle mass in mice by pharmacological inhibition of the myostatin- family ligands, regulating muscle mass growth, rescued C26-cachexia and significantly prolonged survival. Altogether, these data suggest that cancer chemotherapy can promote the development of cachexia and that increasing muscle mass in the occurrence of a tumor might enhance drugs efficacy and safety, thus also prolonging survival. Our hypothesis will be explored by proposing the following aims: 1- Understand the impact of chemotherapy on muscle mass and function. Chemotherapy-associated direct toxicity on skeletal muscle and indirect production of atrophy-associated mediators will be tested in vitro and in vivo. Transcriptomic analysis will identify genes relevant for chemotherapy-induced muscle toxicity. Body composition, muscle functions (grip strength, ex-vivo contractility and fatigability), serum analyte profiling (cytokines, growth factors) and in vitro wasting activity will also be assessed. 2- Determine whether modulation of skeletal muscle mass affects chemotherapy response and tolerability. Mice bearing colorectal tumors (C26, HCT-116) will be receiving chemotherapy and/or ACVR2B/Fc, a peptide that promotes muscle growth. Effect on body composition and muscle functionality, as well as serum analyte profiling will be analyzed. Tumor growth and survival will also be evaluated.

描述（由申请人提供）：本研究计划的主要目的是了解化疗对肌肉质量和功能的影响，探讨肌肉肥大是否可以预防癌症恶病质，提高药物疗效和患者生存率。据推测，除了其他几种副作用外，化疗也是恶病质形成的原因。恶病质，即体重、肌肉和脂肪量的减少，目前还没有治愈方法。这种综合征发生的分子机制已经被研究了一段时间，但是人们对各种癌症治疗对癌症恶病质的影响知之甚少。在这方面，已经有报道称几种抗癌药物可以引起宿主细胞的直接修饰以及诱导负氮平衡。然而，调节这些过程的机制值得进一步关注。我们的初步数据和其他人发表的研究结果支持化疗可能促进肌肉消耗的观点。事实上，化疗药物如顺铂、伊立替康和吉西他滨，广泛用于治疗各种癌症，在体内和体外都会引起剂量依赖性的肌纤维消耗。同样，携带结肠-26和HCT- 116结直肠癌的小鼠也观察到严重的体重减轻和肌肉萎缩。受肌肉消耗影响的癌症患者更容易受到严重的化疗相关毒性的影响，并且与肌肉质量较大的受试者不同，其生存率降低。其他人和我们表明，通过药物抑制肌肉生长抑制素家族配体改善小鼠肌肉质量，调节肌肉质量增长，挽救c26 -恶病质并显着延长生存期。综上所述，这些数据表明癌症化疗可促进恶病质的发展，在肿瘤发生时增加肌肉质量可能会提高药物的疗效和安全性，从而延长生存期。我们的假设将通过提出以下目标来探索：1-了解化疗对肌肉质量和功能的影响。化疗对骨骼肌的直接毒性和间接产生的萎缩相关介质将在体外和体内进行测试。转录组学分析将确定与化疗引起的肌肉毒性相关的基因。还将评估身体组成、肌肉功能（握力、离体收缩力和疲劳性）、血清分析物谱（细胞因子、生长因子）和体外消耗活性。2-确定骨骼肌量的调节是否影响化疗反应和耐受性。结直肠肿瘤（C26, HCT-116）小鼠将接受化疗和/或ACVR2B/Fc（一种促进肌肉生长的肽）。将分析对身体成分和肌肉功能的影响，以及血清分析分析。肿瘤的生长和生存也将被评估。