Targeting the Metabolic Basis of Cachexia in Pancreatic Cancer

项目摘要：胰腺癌是最致命的癌症之一，因为它 广泛转移到远处器官，甚至在肿瘤进展的早期阶段。绝大多数的人 由于恶病质，胰腺癌患者的生活质量也非常差。恶病质不仅仅是 阻碍对化疗的反应，但也是发病率和死亡率的主要原因。因此，一个基本的 了解促进恶病质的机制将为开发新的治疗方法提供基础。 用于治疗，并将显著提高整体生活质量。 肿瘤细胞表现出代谢产物流向生物合成反应的变化，从而诱导全身 导致肌肉变性和脂肪细胞脂肪耗竭的代谢效应。尽管一些研究已经 试图了解肌肉和脂肪降解的机制基础，代谢之间的联系 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 确定在肿瘤组织和肌肉中增加流量的一些关键代谢途径 胰腺癌恶病质患者标本与无恶病质胰腺癌患者标本比较。 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。 不依赖于已知的恶病质制剂。因此，我们假设肿瘤中的代谢流和 分泌的代谢物导致肌肉组织的代谢变化，导致氧化损伤和 恶病质。此外，我们假设靶向肿瘤细胞和 肌肉可以减少胰腺癌患者的恶病质。 为了验证这些假说，我们建议阐明代谢物/代谢途径的直接作用。 在调节恶病质(目标1)中，测试肌肉中的分解代谢通路是否可以被靶向消除 动物模型中的恶病质(目标2)，并确定肌肉组织中代谢物水平升高 胰腺癌患者恶病质发病与预后的相关性(目标3)。我们将验证 恶病质患者血浆中已鉴定的肿瘤细胞分泌代谢物水平升高 癌症患者与非恶病质癌症患者的比较及其机制特征 在动物模型中由这种代谢物引起的直接肌肉退行性变的方面。我们还将确定是否 它们的水平与患者肌肉变性的程度有关。此外，我们建议评估 针对潜在代谢途径减少恶病质的治疗效果。总的来说， 这些研究将利用高度创新的概念和方法来解决代谢物和 癌症恶病质中的代谢途径，并评估靶向这些途径的治疗效果 减少癌症恶病质。

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.