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.

项目名称：线粒体功能障碍是西班牙裔患者治疗相关肝毒性的基础 急性淋巴细胞白血病 抽象的： 急性淋巴细胞白血病是儿童中最常见的癌症类型，在儿童中患病率较高 西班牙裔。虽然急性淋巴细胞白血病 (ALL) 儿童的总生存率已达到约 90%，成年 ALL 患者的结果仍然很差 (<45%)。西班牙裔儿童和青少年 成人（AYA）也都遭受较差的结果。天冬酰胺酶在儿科治疗方案中的大量使用 提高了儿童的治愈率，但成人中天冬酰胺酶相关毒性的发生率较高，限制了其治疗 在这个年龄段广泛使用。肝毒性是一个特别重要的药物引起的禁忌症，因为 当前建议在发生 3 级或 4 级肝毒性时停止天冬酰胺酶治疗， 大约 30% 的 ALL 患者会发生这种情况，可能会影响其治疗效果。西班牙裔患者 与其他种族相比，该族群出现肝毒性的速度更快。肥胖和/或年龄较大的儿童 特别是有肝毒性的风险。不幸的是，天冬酰胺酶在 ALL 中的药物基因组学研究有限 主要针对白人儿科患者。在以非西班牙裔为主的人群中，我们以前 报道称，SOD2 中的基因变异 rs4880 编码一种关键的线粒体酶，可防止 活性氧 (ROS) 与成人 ALL 患者中天冬酰胺酶诱导的肝毒性有关。 高风险 CC 基因型在西班牙裔人群中更为常见，他们也表现出更高的患病率 ALL和天冬酰胺酶引起的肝毒性高于其他种族。在一个主要由西班牙裔人组成的 143 名儿科队列中 在接受基于天冬酰胺酶治疗的 ALL 患者中，我们发现肝酶升高较高 西班牙裔人接受天冬酰胺酶治疗后的比例高于非西班牙裔人。 rs4880 CC 基因型显着 在西班牙裔中也更常见，并且与天冬酰胺酶治疗后肝酶升高有关 西班牙裔患者的体重指数也较高。总而言之，这些数据表明 氧化应激病因涉及多种代谢紊乱，导致与以下相关的肝脏毒性 ALL 患者的天冬酰胺酶。在这里，我们建议探索线粒体酶和 线粒体功能障碍和天冬酰胺酶在西班牙裔中引起肝毒性。我们假设 线粒体功能障碍和氧化应激导致天冬酰胺酶诱导的肝毒性 西班牙裔。我们的目标是： 目标 1) 确定线粒体中促成的遗传和代谢改变 西班牙裔人天冬酰胺酶诱导的肝毒性。目标 2) 开发计算模型来预测 天冬酰胺酶在西班牙裔 ALL 患者中引起的肝毒性。 我们的研究将提供线粒体功能障碍与线粒体功能障碍之间关联的功能证据。 西班牙裔人中天冬酰胺酶相关的肝毒性，并为预测天冬酰胺酶提供了临床上有用的工具 引起西班牙裔 ALL 患者的肝毒性。更广泛地说，我们的发现将揭示机制见解 需要开发降低 ALL 患者毒性并提高疗效的疗法。