CANCAN - Harvard

CANCAN-哈佛

• 批准号: 10625727
• 负责人: NORBERT PERRIMON
• 金额: $ 20.4万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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/10625727
• 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)是一种全身性、代谢性消瘦综合征，其特征是由于骨骼肌和脂肪组织消瘦而导致体重减轻。约80%的癌症患者患有CC，这会导致表现状态下降、对化疗不耐受并增加死亡率。人们对这种衰弱的疾病知之甚少，也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，并延长生存时间。经过50年的研究，该领域专注于确定促进末梢器官萎缩的途径--受恶病质影响最大的器官。虽然这项工作卓有成效，但它并没有导致确定CC的上游介质，也没有产生有效的治疗方法。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，由不同的、国际的、多学科的科学家和临床医生组成，他们拥有癌症、新陈代谢、神经内分泌功能、免疫学、人类代谢性疾病、临床前模型和临床表型方面的专业知识。我们假设CC是由肿瘤内在因素驱动的，这些因素激活神经激素疾病通路，然后导致厌食症、代谢功能障碍和组织萎缩。 方法 我们的方法涉及宿主-肿瘤相互作用的精密测量，包括(1)使用同位素示踪、成像质谱仪、动态核成像以及饮食和药物干预措施，创新地调查了小鼠的全身代谢通量；(2)使用成像质量细胞仪、患者衍生的有机类异种移植、微生物毒素和CRISPR基础操作，研究了肿瘤微环境中的细胞成分和分泌因子；(3)利用人类代谢表型、光遗传学和药理学方法，研究了调节食欲、行为和外周器官代谢的中心通路。我们将在CC受试者中进行最大、最全面的观察性研究，以使用流行病学工具、新的图像分割算法和聚类分析来彻底定义CC亚型及其临床生物标志物。 项目目标 我们的愿景是开发治疗癌症恶病质(CC)的机械信息疗法，以提高患者的生活质量和预期寿命。作为一个在基础科学、临床研究和流行病学方面拥有专业知识的多学科团队，我们将建立CC分子和临床亚型的治疗相关分类。我们将建立治疗方法，使CC的代谢和神经内分泌失调正常化，使患者能够成功地进行抗癌治疗和全身康复。在5年内，我们将为新一代CC治疗试验和战略奠定基础，这些试验和战略将首次提供改变实践的证据，改善有CC风险或患有CC的癌症患者的预后。