Modulating dietary zinc to prevent cachexia and improve survival in cancer

抽象的。 超过80%的转移性癌症患者经历进行性和衰弱的肌肉丧失 质量和功能通过一种称为恶病质的过程来实现。恶病质患者病情恶化 横隔膜和心肌，常因呼吸和心脏衰竭而过早死亡。这个 这些患者往往太虚弱，无法忍受，这进一步降低了他们的预后 标准剂量的抗癌治疗。我们的长期目标是识别和开发潜在的 推动恶病质发展以提高治疗反应、存活率和 转移性癌症患者的生活质量。我们最近发现了肌肉的一种保守机制 在小鼠和转移性癌症患者中的损耗，其中金属离子转运体称为 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，ZIP14的特异性丢失可以缓解恶病质的发展。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 补充剂会加速肌肉萎缩。除了癌症引起的恶病质，我们现在发现 患者常用的某些化疗药物(如阿霉素-环磷酰胺) 和顺铂)也可以引起健康小鼠肌肉中Zip14的上调，而Zip14是 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，化疗药物的子集扰乱了金属离子的动态平衡 并通过上调肌肉细胞中Zip14的表达来促进肌肉萎缩。哪种化疗 药物诱导Zip14，Zip14如何诱导以及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 了解ZIP14在癌症和化疗所致恶病质中的作用。基于 我们的初步研究，在目标1中，我们将确定哪些化疗药物会促进肌肉萎缩。 通过ZIP14轴以及骨桥蛋白，一种来自血清图谱的候选蛋白，是否调节 化疗诱导肌肉细胞表达Zip14。在目标2中，我们将制定战略，以 在转移性癌症模型中防止化疗诱导的、依赖Zip14的肌肉萎缩。 这些研究可以为新的饮食干预策略的开发提供信息，以预防或 逆转恶病质，目的是延长生存时间，提高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。

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.