Modulating dietary zinc to prevent cachexia and improve survival in cancer

调节膳食锌以预防恶病质并提高癌症生存率

• 批准号: 10404596
• 负责人: Swarnali Acharyya
• 金额: $ 36.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404596
• 关键词: Address; Adult; Advanced Malignant Neoplasm; Antibodies; Biochemical; Biological Assay; Biological Models; Blocking Antibodies; Cachexia; Cancer Model; Cancer Patient; Chemotherapy-Oncologic Procedure; Cisplatin; Colon Carcinoma; Cyclophosphamide; Deterioration; Development; Dietary Intervention; Dietary Zinc; Disseminated Malignant Neoplasm; Dose; Doxorubicin; Fatigue; Functional disorder; Goals; Heart failure; Histologic; Homeostasis; Human; In Vitro; Inflammatory; Intervention; Ions; Knockout Mice; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metals; Metastatic breast cancer; Micronutrients; Mission; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Weakness; Muscle function; Muscular Atrophy; Myocardium; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Quality of life; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Role; Serum; Serum Proteins; Signal Pathway; Skeletal Muscle; Supplementation; Symptoms; Testing; Therapeutic; Toxic effect; Up-Regulation; Zinc; Zinc supplementation; anticancer treatment; base; cancer cachexia; cancer therapy; cancer type; chelation; chemotherapeutic agent; chemotherapy; dietary excess; dietary supplements; experience; improved; improved outcome; in vivo; in vivo Model; insight; malignant breast neoplasm; mouse model; muscle form; osteopontin; oxidative damage; patient prognosis; preclinical study; premature; prevent; side effect; therapeutic target; therapy design; treatment response; treatment strategy; tumor

ABSTRACT. More than 80% of metastatic cancer patients experience a progressive and debilitating loss of muscle mass and function by a process known as cachexia. Cachectic patients suffer deterioration of diaphragm and cardiac muscles and often die prematurely due to respiratory and cardiac failure. The prognosis for these patients is further diminished by the fact that they are often too weak to tolerate standard doses of anti-cancer treatments. Our long-term goal is to identify and exploit the underlying mechanisms that drive the development of cachexia to improve treatment response, survival and quality of life in metastatic cancer patients. We recently identified a conserved mechanism of muscle wasting in mice and patients with metastatic cancers in which the metal ion transporter, called SLC39A14 (ZIP14), is upregulated in cachectic muscles (Wang et al., Nat Med, 2018). Muscle- specific loss of ZIP14 alleviates the development of cachexia in these mouse models. Zinc is an essential micronutrient that is often taken as a dietary supplement but in tumor bearing mice, excess supplementation accelerates muscle wasting. In addition to cancer-induced cachexia, we now find that certain chemotherapeutic drugs commonly used in patients (e.g. doxorubicin-cyclophosphamide and cisplatin) can also cause Zip14 upregulation in the muscles of healthy mice and that Zip14 is critical for chemotherapy-induced muscle atrophy in this context. Based on our preliminary studies, our central hypothesis is that a subset of chemotherapeutic drugs perturbs metal-ion homeostasis and promotes muscle wasting through the upregulation of Zip14 in muscle cells. Which chemotherapy agents induce Zip14, how Zip14 is induced and the role of ZIP14 in chemotherapy-induced muscle wasting remains to be explored. The proposed studies are expected to fill this gap and further our understanding of the functions of ZIP14 in cancer- and chemotherapy-induced cachexia. Based on our preliminary studies, in Aim 1, we will determine which chemotherapies promote muscle wasting through the ZIP14 axis and whether Osteopontin, a candidate protein from serum profiling, regulates chemotherapy-induced Zip14 expression in muscle cells. In Aim 2, we will develop strategies to prevent chemotherapy-induced, Zip14-dependent muscle wasting in metastatic cancer models. These studies could inform the development of new dietary intervention strategies to prevent or reverse cachexia, with the aim of prolonging survival, improving treatment response and quality of life in cancer patients with cachexia, in line with the objectives of the PQ11 and NCI.

摘要。 超过80%的转移性癌症患者经历进行性和衰弱性肌肉损失 通过恶病质的过程来发挥作用。恶病质患者的病情恶化， 并且经常由于呼吸和心脏衰竭而过早死亡。的 这些患者的预后由于他们通常太虚弱而不能耐受这一事实而进一步降低 标准剂量的抗癌治疗我们的长期目标是识别和利用潜在的 促进恶病质发展的机制，以改善治疗反应、生存率和 转移性癌症患者的生活质量。我们最近发现了一种肌肉的保守机制， 在小鼠和转移性癌症患者中， SLC39A14（ZIP14）在恶病质肌肉中上调（Wang等人，Nat Med，2018）。肌肉- 在这些小鼠模型中，ZIP 14的特异性缺失加剧了恶病质的发展。锌是一种 必需的微量营养素，通常作为膳食补充剂，但在荷瘤小鼠中，过量 补充会加速肌肉萎缩。除了癌症引起的恶病质外，我们现在发现 通常用于患者的某些化疗药物（例如阿霉素-环磷酰胺 和顺铂）也可引起健康小鼠肌肉中Zip14的上调， 在这种情况下对化疗引起的肌肉萎缩至关重要。根据我们的初步研究， 我们的中心假设是，一个子集的化疗药物扰乱金属离子的稳态 并通过上调肌肉细胞中的Zip14促进肌肉萎缩。哪种化疗 药物诱导Zip14，Zip14如何被诱导以及ZIP14在化疗诱导的肌肉中的作用 浪费仍有待探索。预计拟议的研究将填补这一空白，并进一步促进我们的 了解ZIP14在癌症和化疗诱导的恶病质中的功能。基于 我们的初步研究，在目标1，我们将确定哪些化疗促进肌肉萎缩 通过ZIP14轴，以及骨桥蛋白，一种来自血清分析的候选蛋白，是否调节 化疗诱导的肌肉细胞中的Zip14表达。在目标2中，我们将制定战略， 在转移性癌症模型中预防化疗诱导的Zip14依赖性肌肉萎缩。 这些研究可以为新的饮食干预策略的发展提供信息， 逆转恶病质，目的是延长生存期，改善治疗反应和生活质量 在癌症恶病质患者中，符合PQ11和NCI的目标。