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: 10620225
• 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/10620225
• 关键词: Acceleration; Address; Adult; Advanced Malignant Neoplasm; Antibodies; Biochemical; Biological Assay; Biological Models; Blocking Antibodies; Cachexia; Cancer Model; Cancer Patient; 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; Metastasis Induction; 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; 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; novel therapeutic intervention; 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.

抽象的。 超过 80% 的转移性癌症患者会经历进行性和衰弱性的肌肉丧失 通过称为恶病质的过程来实现质量和功能。恶病质患者病情恶化 膈肌和心肌，经常因呼吸和心力衰竭而过早死亡。这 这些患者的预后进一步恶化，因为他们往往太虚弱而无法忍受 抗癌治疗的标准剂量。我们的长期目标是识别和利用潜在的 驱动恶病质发展的机制，以改善治疗反应、生存和 转移性癌症患者的生活质量。我们最近发现了肌肉的保守机制 小鼠和患有转移性癌症的患者的消瘦，其中金属离子转运蛋白称为 SLC39A14 (ZIP14) 在恶病质肌肉中表达上调 (Wang et al., Nat Med, 2018)。肌肉- ZIP14 的特定缺失减轻了这些小鼠模型中恶病质的发展。锌是一种 必需的微量营养素通常作为膳食补充剂服用，但在荷瘤小鼠中，过量 补充会加速肌肉消耗。除了癌症引起的恶病质外，我们现在发现 患者常用的某些化疗药物（例如阿霉素-环磷酰胺） 和顺铂）也会导致健康小鼠肌肉中 Zip14 上调，并且 Zip14 在这种情况下对于化疗引起的肌肉萎缩至关重要。根据我们的初步研究， 我们的中心假设是化疗药物的一部分会扰乱金属离子稳态 并通过肌肉细胞中 Zip14 的上调促进肌肉萎缩。哪种化疗 药物诱导 Zip14、Zip14 的诱导方式以及 ZIP14 在化疗诱导肌肉中的作用 浪费还有待探讨。拟议的研究预计将填补这一空白并进一步推进我们的研究 了解 ZIP14 在癌症和化疗引起的恶病质中的功能。基于 我们的初步研究，在目标 1 中，我们将确定哪些化疗会促进肌肉萎缩 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 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引起的 Zip14 依赖性肌肉萎缩。 这些研究可以为制定新的饮食干预策略提供信息，以预防或 逆转恶病质，目的是延长生存期、改善治疗反应和生活质量 在患有恶病质的癌症患者中，符合 PQ11 和 NCI 的目标。