Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia

化疗增强癌症恶病质肌肉萎缩的机制

基本信息

批准号：
10550259
负责人：
YI-PING LI
金额：
$ 41.73万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-02 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10550259
关键词：
Address Animals C26 tumor Cachexia Cancer Model Cancer Patient Catabolism Chemosensitization Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Research Colon Carcinoma Complication Data Development Dose Drug usage Etiology FDA approved Fluorouracil Functional disorder Future Genetic Transcription Human Impairment In Vitro Inflammatory Intervention Investigational Therapies Knowledge Lewis Lung Carcinoma Mainstreaming Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Diseases Mitochondria Modeling Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fatigue Muscle Proteins Muscular Atrophy NF-kappa B Omeprazole Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Pilot Projects Proton Pump Inhibitors Quality of life Serum Signal Transduction Skeletal Muscle TLR4 gene Testing Therapeutic Toxic effect Toxicity due to chemotherapy Treatment Protocols Ubiquitin Up-Regulation antagonist cancer cachexia cancer cell cancer survival cancer therapy chemotherapy cytokine design experience extracellular vesicles in vivo mitochondrial dysfunction mortality mouse model multicatalytic endopeptidase complex novel novel therapeutics pharmacologic prevent protein degradation success treatment strategy tumor vesicular release wasting

项目摘要

Summary Chemotherapy is a mainstream treatment for most cancers, despite recent progress in the development of new therapies for cancer. A well-documented long lasting toxicity of some chemotherapy agents is their capacity to cause or intensify muscle wasting and fatigue in cancer patients, which are manifestations of cachexia. Cachexia is a metabolic disorder contributing significantly to cancer-related morbidity and mortality due to systemic wasting, as well as decreasing the efficacy while increasing the toxicity of chemotherapy. Consequently, patients suffering from chemotherapy-related muscle wasting may experience difficulty adhering to or completing treatment regimens and may require delays in treatment, dose limitation, or discontinuation of therapy. Further, chemotherapy-related muscle wasting and fatigue can persist for months to years after the cessation of chemotherapy. Thus, the interplay between chemotherapy and cachexia is a significant threat to cancer patient survival and quality of life. However, the underlying mechanism of the detrimental effects of chemotherapy on skeletal muscle is poorly understood, and there is no FDA-approved treatment for this chemotherapy toxicity. The current proposal aims to address this clinical paradox by testing a novel hypothesis for the mechanism through which fluorouracil (5-FU) and cisplatin, two widely prescribed chemotherapy agents, promote cancer’s capacity to induce muscle wasting in tumor-bearing mice. Previously, supratherapeutic doses of 5-FU were shown to promote muscle dysfunction directly in cancer-free animals by causing mitochondrial dysfunction and oxidative stress but not activating the ubiquitin-proteasome pathway that mediates muscle protein loss. Given that 5-FU is used in cancer patients, it is necessary to understand whether and how 5-FU promotes muscle wasting at therapeutically relevant doses in cancer hosts. Similarly, cisplatin has been shown to cause muscle dysfunction directly in cancer-free mice at a supratherapeutic dose, but whether and how it promotes muscle wasting in cancer hosts are undefined. These knowledge gaps prevent clinical intervention of chemotherapy- associated cachexia. Based on preliminary data, the current project is designed to test the hypothesis that 5- FU and cisplatin cause or intensify muscle wasting in cancer hosts indirectly by stimulating the intrinsic capacity of cancer cells to induce muscle protein degradation at therapeutic doses, and to elucidate the underlying mechanisms of this action. Leveraging these findings, experimental therapies will be carried out by repurposing existing pharmacological agents that inhibit 5-FU and cisplatin’s capacity to stimulate cancer-induced muscle wasting. If successful, these drugs can be quickly tested in clinical settings for intervention of chemotherapy- associated muscle wasting.

概括尽管最近在新疗法的开发方面取得了进展，但化疗仍然是大多数癌症的主流治疗方法一些化疗药物的长期毒性是有据可查的。导致或加剧癌症患者的肌肉萎缩和疲劳，这是恶病质的表现。是一种代谢紊乱，对癌症相关的发病率和死亡率有显着影响，原因是全身性的浪费，以及降低疗效，同时增加所测试的化疗的毒性。患有化疗相关肌肉萎缩的人可能会难以坚持或完成治疗方案，并且可能需要延迟治疗、限制剂量或停止治疗。化疗相关的肌肉萎缩和疲劳可能会在停止化疗后持续数月至数年因此，化疗和恶病质之间的相互作用对癌症患者构成重大威胁。然而，化疗对生存和生活质量产生不利影响的根本机制。人们对骨骼肌知之甚少，而且 FDA 还没有批准针对这种化疗毒性的治疗方法。当前的提案旨在通过测试该机制的新假设来解决这一临床悖论氟尿嘧啶 (5-FU) 和顺铂这两种广泛使用的化疗药物通过氟尿嘧啶 (5-FU) 和顺铂促进癌症的发生此前，5-FU 的超治疗剂量是导致荷瘤小鼠肌肉萎缩的能力。研究表明，通过引起线粒体功能障碍，可直接促进无癌动物的肌肉功能障碍氧化应激但不激活介导肌肉蛋白质损失的泛素蛋白酶体途径。 5-FU 用于癌症患者，有必要了解 5-FU 是否以及如何促进肌肉同样，顺铂已被证明会导致癌症宿主的肌肉萎缩。超治疗剂量下的无癌小鼠的直接功能障碍，但它是否以及如何促进肌肉这些知识差距阻碍了化疗的临床干预。根据初步数据，当前项目旨在检验以下假设：5- FU 和顺铂通过刺激内在能力间接导致或加剧癌症宿主的肌肉萎缩癌细胞在治疗剂量下诱导肌肉蛋白降解，并阐明潜在的机制利用这些发现，实验性疗法将通过重新利用来进行。抑制 5-FU 和顺铂刺激癌症诱发肌肉能力的现有药物如果成功，这些药物可以在临床环境中快速测试以干预化疗。相关的肌肉萎缩。