(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

基本信息

批准号：
8927587
负责人：
Andrea Bonetto
金额：
$ 16.97万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/8927587
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 HCT116 Cells Health 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 cachexia 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 response synthetic peptide transcriptomics tumor tumor growth wasting

项目摘要

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）：该研究建议的主要目标是了解化学疗法对肌肉质量和功能的影响，并研究肌肉肥大是否可以预防癌症恶病质并提高药物疗效和患者的生存。据推测，化学疗法以及其他几种副作用也导致了恶病质的发展。病虫气，即体重，肌肉和脂肪质量的减少，目前尚无治愈。一段时间以来，已经研究了负责该综合征发展的分子机制，但是对各种癌症治疗对癌症恶病质的影响知之甚少。在这条线上，据报道，几种抗癌药可以导致直接的宿主细胞修饰，并引起负氮平衡。但是，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发现支持了化学疗法可能促进肌肉消耗的想法。实际上，诸如顺铂，伊立替康和吉西他滨等化学治疗剂广泛用于治疗不同种类的癌症，导致剂量依赖性的肌肉纤维在体外和体内引起。同样，在带有结肠26和HCT-116结直肠癌的小鼠中观察到严重的体重减轻和肌肉萎缩。受肌肉耗竭影响的癌症患者更容易受到严重化学疗法相关的毒性的影响，并且与肌肉质量较大的受试者不同，生存率降低。其他人，我们表明，通过药理学抑制肌抑制素家族配体，调节肌肉质量生长，营救了C26-核Cachexia并显着延长生存期，可以改善小鼠的肌肉量。总而言之，这些数据表明癌症化学疗法可以促进恶病质的发展，并且在肿瘤发生中增加肌肉质量可能会增强药物的功效和安全性，从而延长生存率。我们的假设将通过提出以下目的来探讨：1-了解化学疗法对肌肉质量和功能的影响。化学疗法相关的直接毒性对骨骼肌和间接产生与萎缩相关的介质的毒性将在体外和体内进行测试。转录组分析将确定与化学疗法诱导的肌肉毒性相关的基因。身体成分，肌肉功能（抓地力，前感染力和疲劳性），血清分析物分析（细胞因子，生长因子）和体外浪费活性也将得到评估。 2-确定骨骼肌质量的调节是否会影响化学疗法反应和耐受性。携带结直肠肿瘤的小鼠（C26，HCT-116）将接受化学疗法和/或ACVR2B/FC，这是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物分析。还将评估肿瘤生长和生存。