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: 9899217
• 负责人: Swarnali Acharyya
• 金额: $ 37.06万
• 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/9899217
• 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; outcome forecast; oxidative damage; 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％的转移性癌症患者经历了肌肉的进行性和使人衰弱的损失 质量和功能通过称为病虫的过程。缓存患者的恶化 diaphragm和心脏肌肉，通常由于呼吸道和心脏衰竭而过早死亡。这 这些患者的预后往往太弱而无法容忍，进一步减少了 抗癌治疗的标准剂量。我们的长期目标是识别和利用基础 驱动恶病质发展以改善治疗反应，生存和的机制 转移性癌症患者的生活质量。我们最近确定了一种保守的肌肉机制 在小鼠和转移性癌症的患者中浪费金属离子转运蛋白，称为 SLC39A14（ZIP14）在缓存的肌肉中被上调（Wang等，Nat Med，2018年）。肌肉- Zip14的特定损失减轻了这些小鼠模型中恶病质的发展。锌是一个 必需的微量营养素，通常被视为饮食补充剂，但在肿瘤轴承小鼠中，过量 补充会加速肌肉浪费。除了癌症引起的缓存外，我们现在发现 患者常用的某些化学治疗药物 和顺铂）也可能导致健康小鼠肌肉的Zip14上调，而Zip14为 在这种情况下，对于化学疗法诱导的肌肉萎缩至关重要。基于我们的初步研究 我们的中心假设是化学治疗药物的子集使金属离子体内稳态降低 并通过肌肉细胞中Zip14的上调促进肌肉浪费。哪种化学疗法 代理诱导Zip14，Zip14的诱导以及Zip14在化学疗法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 了解Zip14在癌症和化学疗法诱导的恶病质中的功能。基于 我们的初步研究，在AIM 1中，我们将确定哪些化学疗法会促进肌肉浪费 通过Zip14轴以及血清分析的候选蛋白骨桥蛋白是否可以调节 化学疗法诱导的肌肉细胞中的Zip14表达。在AIM 2中，我们将制定策略 在转移性癌症模型中预防化学疗法诱导的Zip14依赖性肌肉浪费。 这些研究可以为预防或 反向缓存，以延长生存，改善治疗反应和生活质量 在患有恶病质的癌症患者中，与PQ11和NCI的目标一致。