Mitochondrial Dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia

线粒体功能障碍是西班牙裔急性淋巴细胞白血病治疗相关肝毒性的基础

• 批准号: 10675403
• 负责人: Houda Alachkar
• 金额: $ 44.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675403
• 关键词: Aconitate Hydratase; Acute Lymphocytic Leukemia; Adolescent and Young Adult; Adult; Adult Acute Lymphocytic Leukemia; Aftercare; Alanine Transaminase; Amino Acid Substitution; Amino Acids; Apoptosis; Asparagine; Aspartate Transaminase; Bilirubin; Bioenergetics; Biological; Biological Markers; Body mass index; Caucasians; Cells; Cessation of life; Characteristics; Child; Childhood; Clinical; Cluster Analysis; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Computer Models; Cytoprotection; DNA; Data; Enzymes; Ethnic Origin; Ethnic Population; Etiology; Exhibits; Frequencies; Future; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glutamine; Hepatocyte; Hepatotoxicity; High Prevalence; Hispanic; Hispanic Populations; Hydrogen Peroxide; Impairment; Incidence; Inferior; Link; Lipids; Liver; Los Angeles; Malignant Childhood Neoplasm; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Mutation; Not Hispanic or Latino; Obesity; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Patient risk; Patients; Pediatric Hospitals; Permeability; Pharmaceutical Preparations; Pharmacogenomics; Phase III Clinical Trials; Population; Prevalence; Proteins; Reactive Oxygen Species; Recommendation; Regimen; Reporting; Research; Risk; SOD2 gene; Sampling; Severities; Superoxide Dismutase; Superoxides; Survival Rate; Therapeutic Effect; Toxic effect; Training; Treatment-related toxicity; Underrepresented Populations; age group; antioxidant enzyme; asparaginase; biological adaptation to stress; cancer type; chemotherapy; classification trees; clinical phenotype; cohort; computerized tools; drug induced liver injury; experience; genetic variant; high body mass index; high risk; improved; insight; machine learning method; mitochondrial dysfunction; novel therapeutics; oxidation; pediatric patients; predictive modeling; predictive tools; regression trees; risk variant; therapeutically effective; therapy development; treatment risk; trend; young adult

PROJECT TITLE: Mitochondrial dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia ABSTRACT: Acute Lymphoblastic leukemia is the most common type of cancer in children with higher prevalence in Hispanics. While overall survival for children with acute lymphoblastic leukemia (ALL) has reached approximately 90%, the outcome for adult patients with ALL remains poor (<45%). Hispanic children and adolescent and young adult (AYA) both also suffer inferior outcomes. The intensive use of asparaginase in pediatric regimens has enhanced the cure rate of children, but the higher rate of asparaginase-related toxicity in adults has limited its widespread use in this age group. Hepatotoxicity is a particularly important drug-induced contraindication, as current recommendations of withholding asparaginase treatment when grade 3 or 4 hepatotoxicity develops, which occurs in approximately 30% of ALL patients, may compromise its therapeutic effect. Hispanic patients developed hepatotoxicity at an increased rate compared with other ethnicities. Obese and/or older children are particularly at risk for hepatotoxicity. Unfortunately, pharmacogenomic studies of asparaginase in ALL are limited and mostly focus on Caucasian pediatric patients. In a predominantly non-Hispanic population, we previously reported that genetic variant rs4880 in SOD2, which encodes a key mitochondrial enzyme protective against reactive oxygen species (ROS), is associated with asparaginase-induced hepatotoxicity in adult ALL patients. The high-risk CC genotype is more common in Hispanic individuals, who also exhibit a greater prevalence of ALL and asparaginase-induced hepatotoxicity than other ethnicities. In a largely Hispanics cohort of 143 pediatric patients with ALL who have received asparaginase based regimen, we found higher elevation of liver enzymes post treatment with asparaginase in Hispanics than non-Hispanics. The rs4880 CC genotype was significantly also more frequent in Hispanics and was associated with elevated liver enzymes post asparaginase treatment and higher body mass index which was also higher is Hispanic patients. Altogether, these data suggest an oxidative stress etiology involved in a wide range of metabolic disorders leading to liver toxicities associated with asparaginase in patients with ALL. Here we propose to explore the link between the mitochondrial enzymes and mitochondrial dysfunction and asparaginase induced hepatotoxicity in Hispanics. We hypothesize that mitochondrial dysfunction and oxidative stress contribute to asparaginase-induced hepatotoxicity in Hispanics. Our aims are: Aim 1) Identify genetic and metabolic alterations in the mitochondria that contribute to asparaginase-induced hepatotoxicity in Hispanics. Aim 2) Develop a computational model to predict asparaginase-induced hepatotoxicity in Hispanic patients with ALL. Our study will provide functional evidence of the association between the mitochondrial dysfunction and asparaginase related hepatotoxicity in Hispanics and provide clinically useful tool for predicting asparaginase- induced hepatotoxicity in Hispanic patients with ALL. More broadly, our findings will reveal mechanistic insights needed to develop therapies with reduced toxicity and improved efficacy in patients with ALL.

项目标题：线粒体功能障碍是西班牙裔糖尿病患者治疗相关肝毒性的基础