CANCAN - Cambridge

CANCAN - 剑桥

• 批准号: 10625550
• 负责人: Giulia Biffi
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625550
• 关键词: Text

Background Cancer cachexia (CC) is a systemic, metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status, intolerance to chemotherapy, and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed, it would improve treatment responses, increase quality of life, and prolong survival. With 50 years of study, the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful, it has not led to identification of the upstream mediators of CC, nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse, international, multidisciplinary scientists and clinicians with expertise in cancer, metabolism, neuroendocrine function, immunology, human metabolic diseases, preclinical models, and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways, which then induce anorexia, metabolic dysfunction, and tissue atrophy. Methods Our approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing, imaging mass spectroscopy, dynamic nuclear imaging, and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry, patient-derived organoid xenografts, microbial toxins, and CRISPR-based manipulations; (3) central pathways regulating appetite, behavior, and peripheral organ metabolism using human metabolic phenotyping, optogenetic, and pharmacological methods. We will perform the largest, most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools, novel image segmentation algorithms, and cluster analyses. Project Goals Our vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science, clinical research, and epidemiology, we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years, we will have laid the foundation for a new generation of CC treatment trials and strategies that will, for the first time, deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC.

背景 癌症恶病质（CC）是一种全身，代谢浪费综合征，其体重减轻是由于骨骼肌和脂肪组织浪费而引起的。约80％的癌症患者遭受了CC的痛苦，导致性能状况降低，对化学疗法不耐受和死亡率增加。这种衰弱的状况知之甚少，没有有效的治疗方法。如果存在CC治疗，它将改善治疗反应，提高生活质量并延长生存率。经过50年的研究，该领域的重点是定义途径，这些途径促进受虫病影响最大的最终孔的萎缩。尽管这项工作富有成果，但并未导致CC上游介体的鉴定，也没有产生有效的疗法。迫切需要高质量的发现科学和更详细的临床表型。我们创建了一个虚拟研究所，由多样化的，国际，多学科的科学家和临床医生组成，在癌症，代谢，神经内分泌功能，免疫学，人类代谢疾病，临床前模型和临床表型方面具有专业知识。我们假设CC是由激活神经激素疾病途径的肿瘤内部因素驱动的，然后诱导厌食症，代谢功能障碍和组织萎缩。 方法 我们的方法涉及对宿主肿瘤相互作用的复杂度量，包括使用同位素追踪，成像质谱，动态核成像以及饮食和药理干预措施对小鼠的全身代谢通量进行创新研究； （2）使用成像质量细胞术，患者衍生的类器官异种移植物，微生物毒素和基于CRISPR的操纵的肿瘤微环境中的细胞成分和分泌因子； （3）使用人类代谢表型，光遗传学和药理学方法调节食欲，行为和外周器官代谢的中心途径。我们将使用流行病学工具，新型的图像分割算法和群集分析来彻底定义CC亚型及其临床生物标志物，以彻底定义CC亚型及其临床生物标志物，以彻底定义CC亚型及其临床生物标志物。 项目目标 我们的愿景是为癌症恶病质（CC）开发机械知情的治疗方法，以提高患者的生活质量和预期寿命。作为一个具有基础科学，临床研究和流行病学专业知识的多学科团队，我们将对CC的分子和临床亚型建立与治疗相关的分类。我们将建立疗法，以使CC中的代谢和神经内分泌失调正常化，以实现成功的抗癌治疗和患者的全身恢复。在5年的时间里，我们将为新一代CC治疗试验和策略奠定基础，这些试验和策略将首次提供改变练习的证据，以改善患有CC或患有CC的癌症患者的结局。