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

• 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
• 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

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.

总结 化疗是大多数癌症的主流治疗方法，尽管最近在开发新的化疗药物方面取得了进展。 治疗癌症的方法一些化疗剂的充分记录的持久毒性是它们的能力， 引起或加剧癌症患者的肌肉萎缩和疲劳，这是恶病质的表现。恶病质 是一种代谢性疾病，由于全身性疾病， 浪费，以及降低疗效，同时增加化疗的毒性。因此，患者 患有化疗相关的肌肉萎缩可能会遇到困难，坚持或完成 治疗方案，可能需要延迟治疗、剂量限制或停止治疗。此外，本发明还 停止化疗后，与化疗相关的肌肉萎缩和疲劳可能会持续数月至数年 化疗因此，化疗和恶病质之间的相互作用是癌症患者的重大威胁 生存和生活质量。然而，化疗对肿瘤细胞的有害作用的潜在机制尚不清楚。 对骨骼肌的了解很少，并且没有FDA批准的针对这种化疗毒性的治疗。 目前的建议旨在通过测试一种新的机制假设来解决这一临床矛盾 氟尿嘧啶（5-FU）和顺铂，两种广泛使用的化疗药物，通过这种方式促进癌症的 在荷瘤小鼠中诱导肌肉萎缩的能力。以前，超治疗剂量的5-FU是 显示通过引起线粒体功能障碍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。给定 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 在癌症宿主中以治疗相关剂量消耗。同样，顺铂已被证明会导致肌肉 功能障碍直接在无癌小鼠在超治疗剂量，但它是否以及如何促进肌肉 癌症宿主的消耗是不确定的。这些知识差距阻碍了化疗的临床干预- 相关恶病质根据初步数据，本项目旨在检验5- FU和顺铂通过刺激内在能力间接引起或加剧癌症宿主的肌肉萎缩 在治疗剂量下诱导肌肉蛋白降解，并阐明 这一行动的机制。利用这些发现，实验性疗法将通过重新利用 抑制5-FU和顺铂刺激癌症诱导的肌肉的能力的现有药理学试剂 浪费如果成功，这些药物可以在临床环境中快速测试，用于干预化疗- 相关的肌肉萎缩