Targeting the Metabolic Basis of Cachexia in Pancreatic Cancer

针对胰腺癌恶病质的代谢基础

• 批准号: 10053712
• 负责人: Pankaj Kumar Singh
• 金额: $ 43.41万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-16 至 2022-05-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053712
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Amino Acids; Animal Model; Biomass; Biopsy; Blood Glucose; Cachexia; Cancer Etiology; Cancer Patient; Cancer Prognosis; Cardiopulmonary; Cessation of life; Chemicals; Clinical; Clinical Treatment; Coculture Techniques; Data; Deposition; Diagnostic; Disease; Distant; Eating; Ensure; Ethanolamines; Excision; Failure; Fatty acid glycerol esters; Gene Delivery; Genes; Genetically Engineered Mouse; Glucose; Goals; Hepatic; Homeostasis; Human; Impairment; Intramuscular; Lead; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Metabolic Pathway; Methods; Modeling; Monitor; Morbidity - disease rate; Muscle; Muscle Fibers; Muscular Atrophy; Neoplasm Metastasis; Nutrient; Operative Surgical Procedures; Organ; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Plasma; Play; Prognosis; Quality of life; Reaction; Reactive Oxygen Species; Respiratory Muscles; Role; Sampling; Skeletal Muscle; Specimen; Syndrome; Testing; Tissues; Treatment Efficacy; Tumor Tissue; Tumor stage; United States; X-Ray Computed Tomography; base; cancer cachexia; chemotherapy; combat; improved; innovation; knock-down; knockout gene; metabolic profile; metabolome; metabolomics; mortality; mouse model; muscle form; neoplastic cell; novel; oxidative damage; pancreatic cancer patients; pancreatic neoplasm; prevent; response; skeletal muscle wasting; small molecule; targeted treatment; tumor; tumor metabolism; tumor progression; wasting

Project Summary: Pancreatic adenocarcinomas are among the most fatal cancers because of their extensive metastasis to distant organs, even at an early stage of tumor progression. A significant majority of pancreatic cancer patients also suffer from a very poor quality of life due to cachexia. Cachexia not only impedes the response to chemotherapy but also is a major cause of morbidity and mortality. Thus, a basic understanding of the mechanisms that promote cachexia will provide a basis for developing new methods for treatment and will significantly improve the overall quality of life. Tumor cells display alterations in metabolite flux into biosynthetic reactions that induce systemic metabolic effects causing myodegeneration and adipocyte fat depletion. Although some studies have attempted to understand the mechanistic basis of muscle and fat degradation, the metabolic link between the energy need of tumor cells and cachexia syndrome remains largely unexplored. Our preliminary studies identify a number of key metabolic pathways that have increased flux in tumor tissues and muscle specimens from pancreatic cancer patients with cachexia, in comparison to the ones without cachexia. Furthermore, our results suggest that secreted small-molecule metabolites possess cachectic activity independent of the known cachectic agents. Hence, we hypothesize that metabolic flux in tumors and secreted metabolites lead to metabolic alterations in muscle tissues, causing oxidative damage and cachexia. Furthermore, we hypothesize that targeting the metabolic pathways in tumor cells and muscles will diminish cachexia in pancreatic cancer. To test these hypotheses, we propose to elucidate the direct role of metabolites/metabolic pathways in regulating cachexia (Aim 1), to test if catabolic pathways in muscles can be targeted to abrogate cachexia in animal models (Aim 2), and to determine if elevated levels of metabolites in muscle tissues correlate with cachexia onset and prognosis in pancreatic cancer patients (Aim 3). We will validate the increased levels of identified tumor cell-secreted metabolites in the plasma specimens from cachectic cancer patients in comparison to that of the non-cachectic cancer patients and characterize the mechanistic aspects of direct myodegeneration caused by such metabolites in animal models. We will also determine if their levels correlate with the extent of myodegeneration in patients. Furthermore, we propose to evaluate the therapeutic efficacy of targeting the underlying metabolic pathways for diminishing cachexia. Overall, these studies will utilize highly innovative concepts and approaches to address the role of metabolites and metabolic pathways in cancer cachexia and evaluate the therapeutic efficacy of targeting these pathways to diminish cancer cachexia.

项目摘要：胰腺癌是最致命的癌症之一，因为其 即使在肿瘤进展的早期阶段，也会广泛转移到远处器官。绝大多数 胰腺癌患者还因恶病质而生活质量非常差。不仅恶病质 阻碍化疗的反应，也是发病和死亡的主要原因。因此，一个基本的 了解促进恶病质的机制将为开发新方法提供基础 进行治疗并将显着改善整体生活质量。 肿瘤细胞表现出代谢物流入生物合成反应的变化，从而诱导全身反应 代谢影响导致肌肉变性和脂肪细胞脂肪消耗。尽管一些研究已经 试图了解肌肉和脂肪降解的机制基础，以及之间的代谢联系 肿瘤细胞和恶病质综合征的能量需求在很大程度上仍未被探索。我们的初步研究 确定了一些增加肿瘤组织和肌肉通量的关键代谢途径 患有恶病质的胰腺癌患者的标本与没有恶病质的患者进行了比较。 此外，我们的结果表明分泌的小分子代谢物具有恶病质活性 独立于已知的恶病质剂。因此，我们假设肿瘤中的代谢通量和 分泌的代谢物导致肌肉组织代谢改变，造成氧化损伤 恶病质。此外，我们假设针对肿瘤细胞中的代谢途径 肌肉会减轻胰腺癌的恶病质。 为了检验这些假设，我们建议阐明代谢物/代谢途径的直接作用 调节恶病质（目标 1），测试肌肉中的分解代谢途径是否可以有针对性地消除 动物模型中的恶病质（目标 2），并确定肌肉组织中的代谢物水平是否升高 与胰腺癌患者恶病质发作和预后相关（目标 3）。我们将验证 恶病质血浆样本中已鉴定的肿瘤细胞分泌代谢物的水平增加 癌症患者与非恶病质癌症患者的比较，并描述其机制 在动物模型中由此类代谢物引起的直接肌变性的方面。我们还将确定是否 它们的水平与患者肌变性的程度相关。此外，我们建议评估 针对减少恶病质的潜在代谢途径的治疗效果。全面的， 这些研究将利用高度创新的概念和方法来解决代谢物和 癌症恶病质的代谢途径，并评估针对这些途径的治疗效果 减少癌症恶病质。