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.

项目概要阿霉素是蒽环类化疗药物中的一员，约 60% 的患者使用阿霉素治疗。患有肉瘤、母细胞瘤、白血病和淋巴瘤的小儿癌症患者虽然阿霉素有效。对这些患者非常有效，约 16% 的儿科患者患有阿霉素诱导的心脏毒性 (DIC)，我们最近的研究表明，DIC 会导致需要心脏移植的心力衰竭 2.5 倍。尽管已有 50 多年的研究，但这种现象在非裔美国人 (AA) 儿童癌症幸存者中很常见。目前，在这一领域，预测或预防 DIC 的潜力仍然很小。需要新颖和创新的方法来克服候选基因和全基因组的障碍。主要针对欧洲人的关联研究已鉴定出超过 100 个单核苷酸多态性 (SNP) 与 DIC 具有统计相关性，但由于难以进行实验验证，因此实验验证尚不可行。在我们最近的工作中，我们展示了患者特异性的人类心肌细胞。诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 是患者病情的有效预测因子发生 DIC 的可能性，首次证实 DIC 存在基因组基础。研究发现 hiPSC-CM 可用于三种不同的方式来研究相关的遗传变异在 AA 幸存者中进行 DIC：首先，发现新的预测 SNP；其次，验证 SNP；在目标 1 中，检查调节途径并确定基因型特异性心脏保护方法。我们将从 100 名 AA 儿童癌症成年幸存者中产生具有多种生物协变量的 hiPSC 暴露于阿霉素的患者在体外评估他们对阿霉素的反应，以验证我们之前的发现和在目标 2 中，我们将使用这 100 个患者特定的线来识别药物反应，验证该工具的功能。差异表达、剪接和染色质可及性数量性状位点（deQTL、dsQTL 和 dcaQTL），评估生物协变量，例如阿霉素剂量、癌症诊断年龄、达到年龄、性别、BMI、然后，我们将单独或联合进行放射治疗（胸部除外）和癌症诊断。通过基因组编辑验证这些变异，并从机制上检查 DIC 的致病途径易感性集中于在心肌病、心脏保护和阿霉素中具有已知作用的基因然后，我们将利用上述发现来发现/重新利用基因组信息的心脏保护作用。在目标3中，我们将建立DIC风险预测模型 AA 幸存者结合临床危险因素和上述功能评估的遗传变异，评估其预测性能，在独立的 AA 幸存者中验证它，并在基于网络和用户的总之，这项工作将为我们提供遗传原理。为什么 AA 幸存者会经历 DIC 并通过以下方式提供 1 个经过人类验证的 SNP 数据用于临床应用一个用户友好的工具，以及 2、可以针对 DIC 进行预防的新型心脏保护途径。