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

项目总结/摘要 82%-96%接受化疗（CT）的癌症患者会出现癌症相关疲劳（CRF），并且 这是乳腺癌患者CT最常见的副作用之一。CT引起的CRF是一种令人痛苦的， 与疾病或其治疗相关的持续疲惫感，并对健康结果产生负面影响 (e.g.,抑郁、睡眠障碍、生活质量差）。尽管有各种各样的尝试来研究 CRF的生化机制仍然难以捉摸。这项研究旨在研究分子- 线粒体生物能量学的遗传途径及其与CT诱导的CRF症状的相关性 与接受含CT蒽环类药物治疗的乳腺癌患者相比， 非蒽环类CT。基于蒽环类的CT与线粒体功能障碍有关 通过增加线粒体活性氧（ROS）和诱导的肌肉力量下降。 三磷酸腺苷（ATP）缺乏被认为是疲劳的基础。外周血 疲劳的前列腺癌患者的单个核细胞（PBMC）表现出ATP偶联减少 与没有疲劳的人相比。在接受放疗的前列腺癌患者中，我们 发现CRF的严重程度与线粒体基因的改变显著相关， 线粒体氧化磷酸化（OXPHOS）。在患有CT诱导的乳腺癌患者中， CRF，我们打算确定是否有一个类似的改变表达的肾脏相关基因， PBMCs和血小板中的生物能量学缺陷。我们建议化疗药物（蒽环类- 基于方案）靶向细胞周期进程，其触发遗传和细胞不稳定性，改变表达 线粒体基因和蛋白质，诱导降低电子传递链（ETC）酶活性， 受损的OXPHOS，导致ATP耗竭和过量的ROS产生，导致发展和 强化CRF。这个R21的建议将揭示分子变化之间的联系- 线粒体生物能量学和CT诱导的CRF的遗传途径，当控制相关 协变量具体的目标是：（1）表征与Escherichia相关的基因谱， 接受蒽环类药物CT的乳腺癌患者的CRF症状，与 在基线、中点和CT终点时接受非蒽环类抗生素CT。(2)识别线粒体的轮廓 接受蒽环类药物CT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，与非蒽环类药物为基础的CT患者相比。了解分子- 支持CRF的遗传生物能量学将为有针对性的方法提供新的见解， CT诱发的CRF。这些结果也将推进症状科学，使我们能够发现生物标志物， 治疗药物，支持非药物干预的设计，并启动精确的症状 管理，以改善CRF。

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.