Evaluation of myocardial targets to prevent anthracycline cardiotoxicity in children with Down Syndrome and Leukemia

唐氏综合症和白血病儿童预防蒽环类药物心脏毒性的心肌靶点评价

• 批准号: 10022490
• 负责人: Javier Guillermo Blanco
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022490
• 关键词: Acute Myelocytic Leukemia; Alcohols; Alternative Splicing; Anthracycline; Blood; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Child; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Chromosome 21; Clinical Protocols; Clinical Treatment; Congestive Heart Failure; Data; Daunorubicin; Development; Dose; Down Syndrome; Duborimycin; Embryo; Enzymes; Evaluation; Gene Dosage; Genes; Incidence; Individual; Intervention; Knowledge; Link; Malignant Neoplasms; Modeling; Molecular; Myocardial; Myocardial tissue; Myocardium; Oxidoreductase; Parents; Pathogenesis; Pathway interactions; Patients; Pediatric Oncology Group; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Predisposition; RNA Splicing; Regimen; Reporting; Risk; Role; Signs and Symptoms; Testing; Time; Tissues; Toxic effect; Transcript; Treatment Protocols; Treatment-related toxicity; Troponin; Variant; Work; anti-cancer; base; cardioprotection; design; genome-wide; heart function; heart rhythm; high risk; inter-individual variation; leukemia; novel; pediatric patients; prevent; transcriptome

Children with Down syndrome (DS, trisomy 21) are at increased risk of developing certain cancers. Children with DS have a reported 10-20 fold increased risk of developing acute myeloid leukemia (AML). Anthracycline-based treatment regimens achieve good results in pediatric patients with DS and AML. However, children with AML and DS are at high risk for treatment-related toxicities, including anthracycline-related cardiotoxicity. For example, a report from the Children's Oncology Group documented anthracycline-related cardiomyopathy in 17.5 % of the patients with AML and DS. There is wide inter-individual variability in terms of susceptibility to anthracycline-related cardiotoxicity, and there are no clinical treatments to prevent the development of cardiotoxicity in children with AML and DS. For the past eight years, we have been conducting integrative studies to identify myocardial determinants associated with the pathogenesis of anthracycline cardiotoxicity in individuals with DS. We have shown that the expression of the chromosome 21 gene CBR1 is increased in DS myocardium and results in higher synthesis rates of cardiotoxic anthracycline alcohol metabolites. This is important because anthracycline alcohol metabolites resulting from high CBR1 activity are 40 times more cardiotoxic than parent anthracyclines. These findings have contributed to support the rationale for dose reduction strategies in new clinical protocols implemented by the Children's Oncology Group (trial: AAML0431. Blood, 2017). Novel preliminary data suggest that the expression of DYRK1A, a key chromosome 21 gene associated with various DS phenotypes, is altered in DS myocardium. Our data also suggest that the expressions of 1) embryonic transcript variants of cardiac troponin TNNT2 and 2) the master splicing factor SRp55, are significantly increased in myocardial tissue from individuals with DS. We propose that altered expression of the DYRK1A-SRp55- TNNT2 pathway increases the susceptibility of DS myocardium to the cardiotoxic effects of anthracycline drugs. Studies in Aim 1 will examine the role of the DYRK1A-SRp55-TNNT2 pathway during anthracycline cardiotoxicity in a model of beating cardiomyocytes with trisomy 21. Studies in Aim 2 will examine whether combined pharmacological inhibition of CBR1 and DYRK1A activities protects trisomic cardiomyocytes from the cardiotoxic effects of anticancer anthracyclines. To further investigate determinants for drug induced cardiotoxicity in DS, studies in Aim 3 will define the extent of genome-wide splicing alterations linked to the increased expression of the master splicing factor SRp55 in myocardial tissue from persons with DS. These integrative studies will provide new data for the design of pharmacological interventions to prevent the development of anthracycline cardiotoxicity in pediatric patients with DS and AML.

患有唐氏综合症(DS，21三体)的儿童患某些癌症的风险更高。患有以下疾病的儿童 据报道，DS患急性髓系白血病(AML)的风险增加了10-20倍。以蒽环类为基础的 治疗方案在儿童DS和AML患者中取得了良好的效果。然而，患有AML的儿童 和DS具有治疗相关毒性的高风险，包括与蒽环类药物相关的心脏毒性。为 例如，儿童肿瘤学小组的一份报告记录了与蒽环类药物相关的心肌病 17.5%的AML合并DS患者。就易感性而言，个体间存在广泛的差异性 与蒽环类药物相关的心脏毒性，目前还没有临床治疗方法来预防 急性髓系白血病和DS儿童的心脏毒性。在过去的八年里，我们一直在进行综合研究 确定与蒽环类药物心脏毒性发病机制相关的心肌决定因素 使用DS。我们发现21号染色体基因CBR1在DS心肌中的表达增加。 并导致心脏毒性的蒽环类酒精代谢物的合成速率较高。这一点很重要，因为 高CBR1活性导致的蒽环类酒精代谢产物对心脏的毒性是亲本的40倍 蒽环类药物。这些发现有助于支持新的减少剂量战略的理论基础 儿童肿瘤学小组实施的临床方案(试验：AAML0431。血，2017)。小说 初步数据表明，21号染色体的关键基因DYRK1A的表达与多种疾病有关。 DS表型，在DS心肌中发生改变。我们的数据还表明，1)胚胎的表达 心肌肌钙蛋白TNNT2和2)主要剪接因子SRp55的转录变体显著增加 在DS患者的心肌组织中。我们认为DYRK1A-SRp55的表达改变- TNNT2通路增加DS心肌对蒽环类药物心脏毒性作用的敏感性。 目标1的研究将探讨DYRK1A-SRp55-TNNT2通路在蒽环类药物心脏毒性中的作用。 在一个带有21三体的心肌细胞搏动模型中。AIM 2中的研究将检查联合 药物抑制CBR1和DYRK1A活性保护三体心肌细胞免受心脏毒性 抗癌蒽环类药物的作用。为了进一步研究DS中药物所致心脏毒性的决定因素， AIM 3的研究将确定全基因组剪接改变的程度与增加的表达有关 DS患者心肌组织中的主要剪接因子SRp55。这些综合研究将 为设计预防蒽环类药物发展的药理干预措施提供新数据 儿童DS和AML患者的心脏毒性。