Unraveling the Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer

项目摘要/摘要 接受化疗(CT)的癌症患者中82%-96%会出现癌症相关性疲劳(CRF)，而且 CT在乳腺癌患者中最常见的副作用之一。CT诱发的CRF是一种令人痛苦的， 与疾病或其治疗相关的持续疲劳感，并对健康结果产生负面影响 (例如，抑郁、睡眠障碍、生活质量差)。尽管有各种各样的尝试来调查其病因 CRF的生化机制仍然难以捉摸。这项拟议的研究旨在研究分子- 线粒体生物能量学的遗传途径及其与CT诱导的CRF症状的关系 接受含CT的蒽环类药物治疗的乳腺癌患者与 非基于蒽环类药物的CT。基于蒽环类药物的CT与线粒体功能障碍有关 通过增加线粒体活性氧(ROS)和导致肌肉力量下降。 三磷酸腺苷(ATP)缺乏被认为是疲劳的基础。外周血 前列腺癌疲劳性患者的单个核细胞(PBMC)三磷酸腺苷偶联减少 与那些没有疲劳的人相比，效率更高。在接受放疗的前列腺癌患者中，我们 发现慢性肾功能衰竭的严重程度与线粒体基因改变和受损显著相关 线粒体氧化磷酸化(OXPHOS)。在接受CT诱导的乳腺癌患者中 CRF，我们打算确定线粒体相关基因的表达是否存在类似的变化 PBMC和血小板中存在缺陷的生物能量学。我们建议化疗药物(蒽环类药物-- 基于方案)针对细胞周期进程，这触发了遗传和细胞不稳定，改变了表达 线粒体基因和蛋白质，导致电子传递链(ETC)酶活性降低和 OXPHOS受损，导致ATP耗竭和ROS生成过多，导致发育和 慢性肾功能衰竭的强化。这一R21提议将揭示分子-- 线粒体生物能量学和CT诱导的慢性肾衰的遗传途径 协变量。具体目标是：(1)描述与以下相关的线粒体相关基因的特征 接受基于蒽环类药物CT检查的乳腺癌患者的CRF症状与接受安慰剂扫描的患者相比 CT基线、中点和终点的非基于蒽环类药物的CT。(2)确定线粒体的轮廓 接受基于蒽环类药物CT检查的乳腺癌患者中与CRF症状相关的生物能量学， 在每个时间点，与非基于蒽环类药物的CT患者进行比较。理解分子-- 支持慢性肾衰的遗传生物能量学将提供有针对性的方法所需的新见解，以缓解 CT诱导的慢性肾衰。这一结果还将推动症状科学的发展，使我们能够发现生物标志物，识别 治疗药物，支持非药物干预的设计，并启动精确症状 管理以改善慢性肾功能衰竭。

PROJECT SUMMARY/ABSTRACT Cancer-related fatigue (CRF) occurs in 82%-96% of cancer patients receiving chemotherapy (CT) and it is one of the most prevalent side effects of CT in patients with breast cancer. CT-induced CRF is a distressing, persistent sense of exhaustion related to the disease or its treatment, and negatively impacts health outcomes (e.g., depression, sleep disturbance, poor quality of life). Despite various attempts to investigate the etiology of CRF, the biochemical mechanisms remain elusive. The proposed study aims to investigate the molecular- genetic pathway of mitochondrial bioenergetics and their association with CT-induced CRF symptoms experienced by patients with breast cancer receiving CT-containing anthracyclines, compared to those with non-anthracycline-based CT. Anthracycline-based CT has been associated with mitochondrial dysfunction through increased mitochondrial reactive oxygen species (ROS) and an induced decrease in muscle strength. Deficiency of adenosine triphosphate (ATP) has been proposed as the basis of fatigue. Peripheral blood mononuclear cells (PBMCs) of fatigued patients with prostate cancer has exhibited reduced ATP coupling efficiency compared to those without fatigue. In patients with prostate cancer undergoing radiotherapy, we found that CRF severity was significantly correlated with altered mitochondrial genes and impaired mitochondrial oxidative phosphorylation (OXPHOS). In patients with breast cancer suffering from CT-induced CRF, we intend to determine whether there is a similar altered expression of mitochondrial-related genes with defective bioenergetics in PBMCs and platelets. We propose that the chemotherapeutic agent (anthracycline- based regimen) targets cell cycle progression, which triggers genetic and cellular instability, altering expression of mitochondrial genes and proteins, inducing reduced electron transport chain (ETC) enzymatic activity and impaired OXPHOS, resulting in ATP depletion and excessive ROS generation, leading to the development and intensification of CRF. This R21 proposal will reveal the linkage between changes in the molecular- genetic pathway of mitochondrial bioenergetics and CT-induced CRF when controlling for relevant covariates. Specific aims are to: (1) Characterize the profile of mitochondria-related genes associated with CRF symptoms in patients with breast cancer receiving anthracycline-based CT, compared to patients with non-anthracycline-based CT at baseline, midpoint, and endpoint of CT. (2) Identify the profile of mitochondrial bioenergetics associated with CRF symptoms in patients with breast cancer receiving anthracycline-based CT, compared to patients with non-anthracycline-based CT, at each time point. Understanding the molecular- genetic bioenergetics underpinning CRF will provide novel insights needed for targeted approaches to mitigate CT-induced CRF. The results will also advance symptom science, enable us to discover biomarkers, identify therapeutic agents, support the design of nonpharmacological interventions, and initiate precision symptom management to improve CRF.