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

揭示乳腺癌患者分子遗传学生物能学与化疗引起的疲劳症状之间的关联

• 批准号: 10525505
• 负责人: Chao-Pin Hsiao
• 金额: $ 24.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525505
• 关键词: Adenosine Triphosphate; Adverse effects; Affective; Anthracycline; Antibiotics; Behavior; Behavioral; Biochemical; Bioenergetics; Biological Markers; Blood Platelets; Breast Cancer Patient; Breast Cancer Treatment; Cancer Etiology; Cancer Patient; Cardiotoxicity; Cell Cycle Progression; Cells; Chemotherapy-Oncologic Procedure; Chronic Fatigue Syndrome; Cognitive; Complex; Coupling; Defect; Development; Dimensions; Disease; Distress; Dose; Doxorubicin; Elderly; Electron Transport; Energy Metabolism; Equilibrium; Esophageal Adenocarcinoma; Exhibits; Fatigue; Foundations; Gene Expression; Gene Proteins; Generations; Genes; Genetic; Health; Heterogeneity; Impaired cognition; Impairment; Individual; Injury; Interruption; Intervention; Investigation; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mental Depression; Mitochondria; Mitotic; Molecular Genetics; Motivation; Mus; Muscle; Myocardium; Neuropathy; Normal tissue morphology; Nutraceutical; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Quality of life; Radiation therapy; Reactive Oxygen Species; Regimen; Reporting; Research Project Grants; Respiratory Chain; Sensory; Severities; Sleep disturbances; Symptoms; Therapeutic Agents; Time; Tissues; Toxic effect; base; cancer biomarkers; chemotherapeutic agent; chemotherapy; cognitive function; design; diagnostic biomarker; exhaustion; experience; health related quality of life; heart function; improved; insight; malignant breast neoplasm; mitochondrial dysfunction; muscle strength; novel; personalized management; preclinical study; reduced muscle strength; side effect; symptom management; symptom science; targeted agent; therapeutic target; therapeutically effective; tumor

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.

项目总结/文摘