Genomic Prediction of Doxorubicin-Induced Cardiotoxicity

阿霉素引起的心脏毒性的基因组预测

基本信息

批准号：
10456312
负责人：
Paul W. Burridge
金额：
$ 33.23万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-13 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456312
关键词：
Affect Age Algorithms Anthracycline Attenuated Biochemical Bioinformatics Biological Biological Assay Biopsy Blastoma CRISPR/Cas technology Cancer Patient Candidate Disease Gene Cardiac Myocytes Cardiomyopathies Cardiotonic Agents Cardiotoxicity Cells Clinical Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Complication Correlation Studies Data Disadvantaged Dose Doxorubicin Etiology Exposure to Gene Expression Genes Genetic Genetic Markers Genetic study Genome Genomics Genotype Heart Transplantation Heart failure Human In Vitro Individual Knock-out Knowledge Lead Malignant Childhood Neoplasm Maps Mediating Metabolism Methodology Modality Molecular Mutation Oncologist Organ Pathway interactions Patients Pediatric cohort Pharmaceutical Preparations Phenotype Physiological Population Predisposition Process Quantitative Trait Loci RARG gene Reproducibility Research Research Personnel Resistance Role Route Single Nucleotide Polymorphism Solid Neoplasm Time Translating Untranslated RNA Validation Variant Work alternative treatment base cancer diagnosis cardioprotection chemotherapy clinical application cohort differential expression experience gene discovery genetic variant genome editing genome wide association study genomic tools human model induced pluripotent stem cell derived cardiomyocytes innovation interest leukemia/lymphoma lymphoblastoid cell line novel patient response pediatric patients prevent recruit response sarcoma screening sex side effect tool transcriptome transcriptome sequencing whole genome

项目摘要

Project Summary The anthracycline doxorubicin used in approximately 60% of pediatric cancer patients with metastatic solid tumors (sarcomas), blastomas, leukemia, and lymphoma. Treatments using doxorubicin are complicated by its well-established cardiotoxic side effect, which affects approximately 16% of pediatric patients, can lead to heart failure requiring heart transplant, and limits doxorubicin’s clinical utilization. Despite more than 50 years of research in this field, there is still, at present, little potential for either predicting or preventing cardiotoxicity. There is an obvious need for novel and innovative approaches to overcome this hurdle. Candidate gene association studies and genome–wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) that are statistically correlated with doxorubicin–induced cardiotoxicity (DIC), yet experimental validation of these SNPs 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–CM) are efficient predictors of a patient’s likelihood of developing DIC, confirming for the first time that there is a genomic basis to DIC. Although GWAS has proven to be a powerful methodology for informing such genomic bases, it detects correlation rather than causation, and identified SNPs commonly fail to be replicated in subsequent studies. Here, we hypothesize that hiPSC-CMs can be utilized in three different modalities to study genetic variants associated with DIC: 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 recruit 100 pediatric cancer patients who were exposed to doxorubicin and assess the response of patient-derived hiPSC-CM to doxorubicin in vitro to validate our previous findings in a large pediatric cohort with diverse biological covariates to verify the power of this tool. In Aim 2, we will use these 100 patient-specific lines to identify drug response differential expression quantitative trait loci (deQTL), assessing biological covariates such as dose, age, sex, SF, 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. In Aim 3, we will interrogate the rigor and reproducibility of >40 existing DIC SNP studies, using CRISPR/Cas9 to edit the gene of interest in control isogenic hiPSC lines then assess the response of hiPSC-CM to doxorubicin. We will then use the discoveries above to discover/repurpose genome-informed cardioprotective drugs to prevent DIC in a genotype-specific manner. In summary, this work will deliver us the genetic rationale for why patients experience DIC and provide 1, fully human validated SNP data for clinical application, and 2, novel cardioprotective drugs to attenuate DIC.

项目摘要大约60％的儿科癌症患者中使用的蒽环类告道精用于转移性固体的患者肿瘤（肉瘤），胚泡，白血病和淋巴瘤。使用阿霉素的治疗由其汇总公认的心脏毒性副作用影响了大约16％的小儿患者，可能会导致心脏需要心脏移植的失败，限制阿霉素的临床利用。尽管超过50年在该领域的研究，目前仍然没有预测或预防心脏毒性的潜力。那里显然需要新颖和创新的方法来克服这一障碍。候选基因关联研究和基因组范围的关联研究（GWAS）已经确定了许多单核苷酸多态性（SNP）在统计上与阿霉素诱导的心脏毒性（DIC）相关，但实验验证由于难以在体外隔离和培养人类心肌细胞，因此这些SNP不可行。在我们最近的工作中，我们表明患者特异性人类诱导的多能干细胞衍生心肌细胞（HIPSC – CM）是患者患DIC的可能性的有效预测指标第一次有DIC的基因组基础。尽管GWAS已被证明是一种有力的方法论告知此类基因组基础，它检测到相关性而不是原因，并且发现SNP通常失败在随后的研究中得到复制。在这里，我们假设可以在三种不同的地方使用HIPSC-CMS 研究与DIC相关的遗传变异的方式：首先，发现新颖的预测SNP；其次，要验证SNP；第三，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，我们将招募100名暴露于阿霉素并评估患者衍生的HIPSC-CM对阿霉素的反应，以验证我们的先前与潜水员生物协变量的大儿科队列中的发现，以验证该工具的功能。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异表达定量性状基因座（DEQTL），评估剂量，年龄，性别，科幻小说和癌症诊断等生物学协变量的单独和合并。然后，我们将通过基因组编辑验证这些变体，并机械检查途径 DIC易感性集中在心肌病，心脏保护中已知作用的基因上，和阿霉素代谢。在AIM 3中，我们将询问> 40现有DIC SNP的严谨性和可重复性研究，使用CRISPR/CAS9编辑控制ISEGENIC HIPSC线的感兴趣基因，然后评估响应 HIPSC-CM到阿霉素。然后，我们将使用上面的发现来发现/重新利用基因组信息心脏保护药物以特异性方式预防DIC。总而言之，这项工作将为我们提供遗传理由是为何患者出现DIC并提供1个完全人类验证的SNP数据以进行临床应用和2个新型心脏保护药物减弱DIC。