CANCAN - ROCHESTER

康康 - 罗切斯特

• 批准号: 10845755
• 负责人: KAREN M. MUSTIAN
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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/10845755
• 关键词: Address; Adipose tissue; Affect; Algorithmic Analysis; Animals; Anorexia; Atlases; Atrophic; Autophagocytosis; Basic Science; Behavior; Biological Markers; Blood; Body Composition; Body Weight decreased; Cachexia; Cancer Etiology; Cancer Model; Cancer Patient; Catabolic Process; Cells; Characteristics; Classification; Clinic; Clinical; Clinical Research; Clinical Trials; Cluster Analysis; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Cytometry; Data; Desire for food; Diagnosis; Eating; Endocrine; Energy Metabolism; Epidemiology; Etiology; Fatty acid glycerol esters; Feeding behaviors; Foundations; Future; GDF15 gene; Gene Expression Profiling; Generations; Genes; Genetic; Geography; Goals; High-Risk Cancer; Histologic; Hormonal; Hormones; Human; Image; Immune; Immunology; Inflammatory; Inflammatory Response; Interleukin-6; International; Intervention; Intrinsic factor; Investigation; Isotopes; Lead; Life Expectancy; Link; Lipolysis; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Mediator; Medical; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Mus; Muscle; Neuroendocrinology; Neurologic; Neurosecretory Systems; Non-Small-Cell Lung Carcinoma; Nutrient; Observational Study; Organ; Organoids; Pathway interactions; Patient Recruitments; Patient-Focused Outcomes; Patients; Performance Status; Peripheral; Phenotype; Physical Function; Physiological; Pre-Clinical Model; Prospective, cohort study; Quality of life; Recovery; Risk; Science; Scientist; Skeletal Muscle; Specialist; System; Therapeutic; Time; Tissues; Toxin; Translations; Ubiquitin; Validation; Vision; Wasting Syndrome; Whole Organism; Work; Xenograft procedure; anorexic; anticancer treatment; behavioral study; cancer cachexia; cancer risk; cancer therapy; carcinogenesis; chemotherapy; clinical biomarkers; clinical care; clinical phenotype; clinical subtypes; clinically relevant; cohort; cytokine; dietary; effective therapy; gut microbiome; host neoplasm interaction; imaging Segmentation; improved; improved outcome; in vivo; innovation; insulin signaling; lung microbiome; metabolic phenotype; microbial; microbiome; microbiota; molecular subtypes; mortality; mouse model; multicatalytic endopeptidase complex; multidisciplinary; neoplastic cell; novel; nuclear imaging; optogenetics; patient population; pharmacologic; recruit; response; tool; treatment response; treatment strategy; treatment trial; tumor; tumor metabolism; tumor microenvironment; tumor progression; uptake; virtual; wasting

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