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; 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：线粒体功能障碍是与治疗相关的西班牙裔肝毒性的基础 急性淋巴细胞白血病 抽象的： 急性淋巴细胞白血病是患有较高患病率的儿童中最常见的癌症类型 西班牙裔。急性淋巴细胞白血病（ALL）的儿童的总体生存率已大约达到 90％，成年患者的结果仍然很差（<45％）。西班牙裔儿童和青少年和年轻 成人（AYA）都遭受较低的结果。天冬酰胺酶在小儿方案中的密集使用 提高了儿童的治愈率，但是成年人与天冬酰胺酶相关的毒性的较高率限制了 这个年龄段的广泛使用。肝毒性是一个特别重要的药物引起的禁忌症，因为 当3或4级肝毒性形成时，预扣天冬酰胺酶处理的当前建议， 大约30％的患者可能会损害其治疗作用。西班牙裔患者 与其他种族相比，开发的肝毒性速度更高。肥胖和/或年龄较大的孩子 特别是有肝毒性的风险。不幸的是，在所有有限的天冬酰胺酶的药物基因组学研究 主要专注于高加索儿科患者。在主要非西班牙裔人口中，我们以前 报道了SOD2中的遗传变异RS4880，它编码关键的线粒体酶保护反对 活性氧（ROS）与所有患者中天冬酰胺酶诱导的肝毒性有关。 高风险的CC基因型在西班牙裔人中更为常见，他们也表现出更大的流行率 与其他种族相比，所有和天冬氨酸酶诱导的肝毒性。在大部分西班牙裔人群中，由143个小儿组成 所有接受过天冬氨酸酶方案的患者，我们发现肝酶升高较高 西班牙裔中天冬酰胺酶的治疗比非西班牙裔治疗。 RS4880 CC基因型显着 在西班牙裔中也更加频繁，并且与肝酶升高有关，在白云母酶治疗后 较高的体重指数也更高的是西班牙裔患者。总共，这些数据表明 氧化应激病因涉及广泛的代谢疾病，导致肝毒性与 所有患者天冬酰胺酶。在这里，我们建议探索线粒体酶与 线粒体功能障碍和天冬酰胺酶在西班牙裔中诱导肝毒性。我们假设这一点 线粒体功能障碍和氧化应激有助于天冬酰胺酶诱导的肝毒性 西班牙裔。我们的目标是：目标1）确定有助于线粒体中的遗传和代谢改变 白天酶诱导西班牙裔肝毒性。目标2）开发一个计算模型来预测 天冬酰胺酶诱导的西班牙裔患者诱导的肝毒性。 我们的研究将为线粒体功能障碍与 天冬氨酸酶相关的西班牙裔肝毒性，并为预测天冬氨酸酶 - 所有人的西班牙裔患者诱导了肝毒性。更广泛地说，我们的发现将揭示机械见解 需要开发毒性降低并提高所有患者疗效的疗法。