Novel Biomarkers for Cancer-Related Fatigue: Integrating Metabolomics, Genomics and Behaviors

癌症相关疲劳的新型生物标志物：整合代谢组学、基因组学和行为

• 批准号: 9973799
• 负责人: Jane C. Figueiredo
• 金额: $ 73.43万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-28 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973799
• 关键词: Address; Adherence; Affect; Aftercare; Age; Behavior; Behavioral; Behavioral Mechanisms; Biological; Biology; Blood specimen; Cancer Biology; Cancer Etiology; Cancer Patient; Cancer Survivor; Catabolism; Ceramides; Characteristics; Chronic; Chronic Fatigue Syndrome; Circadian Dysregulation; Circadian Rhythms; Clinical; Cohort Studies; Collaborations; Colorectal Cancer; Complex; Data; Diagnosis; Diet; Energy Metabolism; Epidemiology; Evaluation; Exercise; Fatigue; Functional disorder; Genes; Genetic Variation; Genome; Genomics; Guidelines; Individual; Inflammasome; Inflammation; Inflammatory; International; Intervention; Life; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; National Comprehensive Cancer Network; Neurosecretory Systems; Omega-3 Fatty Acids; Operative Surgical Procedures; Pathway interactions; Patient Self-Report; Patients; Pattern; Physical activity; Precipitating Factors; Predisposing Factor; Predisposition; Prevention; Production; Quality of life; Reporting; Research; Risk; Ritalin; Role; Science; Site; Sleep; Sleep disturbances; Survivors; Symptoms; System; Technology; Therapeutic Intervention; Time; Treatment-Related Cancer; Tryptophan; Work; biobehavior; biological sex; cancer biomarkers; cancer therapy; chemotherapy; cohort; colon cancer patients; comorbidity; cytokine; experience; genetic variant; genomic variation; high risk; inflammatory marker; innovation; lipid mediator; metabolome; metabolomics; multiple omics; novel marker; novel strategies; personalized medicine; physical inactivity; prospective; psychosocial; small molecule; survivorship; targeted treatment; uptake

PROJECT SUMMARY From initial diagnosis through treatment and into survivorship, patients frequently report fatigue as a significant problem. Studies suggest that up to 90% of cancer patients experience moderate to severe fatigue during treatment and nearly 30% after treatment completion. Fatigue pathophysiology is thought to be multifactorial and complex, including host susceptibility, pro-inflammatory cytokine production, disruption in circadian rhythms of sleep/activity patterns, and neuroendocrine and metabolic dysregulation. However, to date most studies examining the biology of cancer-related fatigue have limited their focus to inflammation. We propose a new approach, the Predisposing, Precipitating, and Perpetuating (3P) model, to comprehensively examine cancer- related fatigue pathophysiology. The 3P model hypothesizes that: (1) genetic variants predispose patients to fatigue, (2) inflammation and metabolic dysregulation caused by cancer and its treatment are precipitating factors, and (3) behaviors such as poor diet, physical inactivity, and sleep disruption perpetuate the problem. In the current study, we will use a metabolomics approach, the study of small molecules, to examine the relative contributions of precipitating endogenous metabolism and cytokines as well as perpetuating behavioral factors to fatigue pathophysiology, and how these are modified by predisposing genetic variants and other factors. This approach offers an exciting opportunity to interrogate cancer-related fatigue at a multi-omics systems level. To our knowledge, cancer-related fatigue has never been studied in the context of the metabolome. We will leverage detailed clinical, epidemiological, and objective and subjective behavioral data as well as blood samples obtained at diagnosis/surgery and sequentially up to 2-years post-diagnosis from the ColoCare Study, a large, international, multi-site, prospective colorectal cancer (CRC) survivor cohort (n=2,379) to determine and validate predictors of fatigue. The ColoCare study is the only large cohort study that collects such comprehensive biological and behavioral data in the context of CRC. The study has three aims. In Aim 1, we will examine genomic variation and other baseline characteristics as predisposing factors for cancer-related fatigue. In Aim 2, we will examine the metabolome and inflammasome as precipitating factors for cancer-related fatigue. In Aim 3, we will conduct an integrative analysis to evaluate sleep, physical activity, diet, and their relationships with the genome, metabolome and inflammasome as perpetuating factors for cancer-related fatigue. This study is unique in using the 3P framework, detailed longitudinal evaluation of fatigue, and use of cutting-edge technologies to measure multi-omic and behavioral changes over time. Results will provide new avenues for risk prediction, prevention, and treatment of cancer-related fatigue.

项目概要 从最初的诊断到治疗再到生存，患者经常报告疲劳是一个重要的因素 问题。研究表明，高达 90% 的癌症患者在治疗期间会经历中度至重度疲劳。 治疗完成后接近 30%。疲劳病理生理学被认为是多因素影响的 复杂，包括宿主易感性、促炎细胞因子的产生、昼夜节律的破坏 睡眠/活动模式以及神经内分泌和代谢失调。然而，迄今为止大多数研究 对癌症相关疲劳的生物学研究将他们的注意力限制在炎症上。我们提出一个新的 方法，即诱发、诱发和永久 (3P) 模型，全面检查癌症 相关的疲劳病理生理学。 3P 模型假设：（1）遗传变异使患者易于 疲劳，（2）癌症及其治疗引起的炎症和代谢失调正在加剧 因素，以及（3）不良饮食、缺乏身体活动和睡眠中断等行为使问题长期存在。在 在当前的研究中，我们将使用代谢组学方法，即小分子的研究，来检查相对 促进内源代谢和细胞因子以及持续行为因素的贡献 疲劳的病理生理学，以及如何通过易感基因变异和其他因素来改变这些。这 该方法提供了一个令人兴奋的机会，可以在多组学系统水平上探究与癌症相关的疲劳。到 据我们所知，癌症相关的疲劳从未在代谢组的背景下进行过研究。我们将利用 详细的临床、流行病学、客观和主观行为数据以及获得的血液样本 诊断/手术时以及诊断后长达 2 年的 ColoCare 研究是一项大型、 国际、多地点、前瞻性结直肠癌 (CRC) 幸存者队列 (n=2,379) 以确定和验证 疲劳的预测因素。 ColoCare 研究是唯一收集如此全面信息的大型队列研究 CRC 背景下的生物学和行为数据。该研究有三个目标。在目标 1 中，我们将检查 基因组变异和其他基线特征是癌症相关疲劳的诱发因素。在目标 2 中， 我们将检查代谢组和炎症小体作为癌症相关疲劳的诱发因素。在目标 3 中， 我们将进行综合分析来评估睡眠、身体活动、饮食及其与身体的关系 基因组、代谢组和炎症体是癌症相关疲劳的持久因素。这项研究是独一无二的 使用3P框架、详细的纵向疲劳评估以及使用尖端技术来 测量多组学和行为随时间的变化。结果将为风险预测提供新途径， 预防和治疗癌症相关的疲劳。