Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children

预测和预防非裔美国儿童化疗引起的心脏毒性

基本信息

批准号：
10275329
负责人：
Paul W. Burridge
金额：
$ 68.45万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10275329
关键词：
ATAC-seq Adolescent Adult Affect African American Age Algorithms American Anthracycline Area Biochemical Biological Biological Assay Blastoma Body mass index CRISPR/Cas technology Cancer Patient Candidate Disease Gene Cardiac Myocytes Cardiomyopathies Cardiotoxicity Chest Child Chromatin Clinical Clinical Data Clinical Research Common Terminology Criteria for Adverse Events Complication Correlation Studies Coupled Cryopreservation Data Detection Dose Doxorubicin Drug Prescriptions Drug usage Enhancers Etiology European Exposure to Gene Expression Genes Genetic Genetic study Genome Genomics Genotype Heart Transplantation Heart failure Hematologic Neoplasms High Prevalence Human In Vitro Individual Knowledge Lead Linkage Disequilibrium Malignant Childhood Neoplasm Mediating Metabolism Methodology Modality Oncologist Online Systems Participant Pathway interactions Patients Performance Pharmaceutical Preparations Phenotype Physiological Predisposition Process Quantitative Trait Loci RARG gene RNA Splicing Radiation therapy Regulatory Element Research Risk Risk Factors Role Route Saint Jude Children&apos s Research Hospital Sampling Single Nucleotide Polymorphism Solid Survivors Time Translating Validation Variant Work alternative treatment base cancer diagnosis cardioprotection chemotherapy childhood cancer survivor clinical application clinical risk cohort differential expression epigenome experience genetic variant genome editing genome sequencing genome wide association study genomic tools human model induced pluripotent stem cell innovation interest leukemia/lymphoma member novel pediatric patients prevent promoter racial disparity response risk prediction risk prediction model sarcoma sex tool transcriptome transcriptome sequencing user-friendly whole genome

项目摘要

Project Summary Doxorubicin is a member of the anthracycline group of chemotherapy drugs prescribed to approximately 60% of pediatric cancer patients suffering with sarcomas, blastomas, leukemia, and lymphoma. Although doxorubicin is highly effective in these patients, ~16% of pediatric patients suffer doxorubicin-induced cardiotoxicity (DIC) which can lead to heart failure requiring heart transplant. Our recent work has shown that DIC is 2.5x more prevalent in African American (AA) survivors of childhood cancer. Despite more than 50 years of research in this field, there is still, at present, little potential for either predicting or preventing DIC. There is an obvious need for novel and innovative approaches to overcome this hurdle. Candidate gene and genome-wide association studies, predominantly in Europeans, have identified >100 single nucleotide polymorphisms (SNPs) that are statistically correlated with DIC, yet experimental validation has not been feasible due to the difficulty in isolating and culturing human cardiomyocytes in vitro. In our recent work, we showed that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are efficient predictors of a patient’s likelihood of developing DIC, confirming for the first time that there is a genomic basis to DIC. Here, we hypothesize that hiPSC-CMs can be utilized in three different modalities to study genetic variants associated with DIC in AA survivors: firstly, to discover novel predictive SNPs; secondly, to validate SNPs; and thirdly, to examine the modulated pathways and determine genotype-specific cardioprotective methodologies. In Aim 1, we will generate hiPSC from 100 AA adult survivors of childhood cancer with diverse biological covariates who were exposed to doxorubicin assess their response to doxorubicin in vitro to validate our previous findings and verify the power of this tool. In Aim 2, we will use these 100 patient-specific lines to identify drug response differential expression, splicing and chromatin accessibility quantitative trait loci (deQTL, dsQTL and dcaQTL), assessing biological covariates such as doxorubicin dose, age at cancer diagnosis, attained age, sex, BMI, radiotherapy (other than involving chest), and cancer diagnosis both individually and combined. We will then validate these variants with genome editing, and mechanistically examine pathways causative to DIC susceptibility concentrating on genes with known roles in cardiomyopathy, cardioprotection, and doxorubicin metabolism. We will then use the discoveries above to discover/repurpose genome-informed cardioprotective drugs to prevent DIC in a genotype-specific manner. In Aim 3, we will build a risk prediction model for DIC among AA survivors incorporating clinical risk factors and functionally assessed genetic variants above, evaluate its prediction performance, validate it in independent AA survivors, and implement it in a web-based and user- friendly tool for broader clinical and research use. In summary, this work will deliver us the genetic rationale for why AA survivors experience DIC and provide 1, fully human validated SNP data for clinical application through a user-friendly tool, and 2, novel cardioprotective pathways that can be targeted to protect against DIC.

项目摘要阿霉素是处方约60％的化学疗法药物的蒽环类药物组的成员患有肉瘤，卵裂瘤，白血病和淋巴瘤患者的儿科癌症患者。虽然阿霉素是在这些患者中非常有效，约有16％的小儿患者患有阿霉素诱导的心脏毒性（DIC）可能导致心力衰竭需要心脏移植。我们最近的工作表明，DIC越多2.5倍在非裔美国人（AA）儿童癌症中流行。尽管研究了50多年在这个领域，目前仍然没有预测或预防DIC的潜力。有一个明显的需要新颖和创新的方法来克服这一障碍。候选基因和全基因组协会研究主要在欧洲人中确定> 100个单核苷酸多态性（SNP）在统计上与DIC相关，但由于难度，实验验证是不可行的在体外分离和培养人类心肌细胞。在我们最近的工作中，我们证明了特定于患者的人诱导多能干细胞衍生的心肌细胞（HIPSC-CMS）是患者的有效预测指标开发DIC的可能性首次确认DIC存在基因组基础。在这里，我们假设可以在三种不同的方式中使用HIPSC-CMS来研究相关的遗传变异在AA表面上使用DIC：首先，发现新颖的预测SNP；其次，验证SNP；第三，要检查调制途径并确定基因型特异性心脏保护方法。在AIM 1中，我们将与潜水员生物协变量的100个AA成人儿童癌症生存产生HIPSC 暴露于阿霉素评估中对阿霉素的反应，以验证我们以前的发现和验证该工具的功能。在AIM 2中，我们将使用这100条患者特异性线来识别药物反应差分表达，剪接和染色质可访问性定量性状基因座（DEQTL，DSQTL和DCAQTL），评估生物学协变量，例如阿霉素剂量，癌症诊断年龄，年龄，性别，性别，bmi，放射疗法（除了胸部以外）和癌症诊断，既单独又合并。然后我们会通过基因组编辑验证这些变体，并机械检查途径谨慎易感性集中在心肌病，心脏保护和阿霉素中已知作用的基因代谢。然后，我们将使用上面的发现来发现/重新利用基因组信息保护以基因型特异性方式预防DIC的药物。在AIM 3中，我们将在AIM 3中为DIC建立风险预测模型 AA表面融合了临床风险因素并在功能上评估了上面的遗传变异，评估了其预测性能，在独立的AA表面上验证它，并在基于Web的用户和用户中实现用于更广泛的临床和研究用途的友好工具。总而言之，这项工作将为我们提供遗传原理为什么AA冲浪者会经历DIC并通过1个完全人为验证的SNP数据进行临床应用一个用户友好的工具和2个新颖的心脏保护途径，可以针对防止DIC。