Genomic Prediction of Doxorubicin-Induced Cardiotoxicity

阿霉素引起的心脏毒性的基因组预测

• 批准号: 10524092
• 负责人: Paul W. Burridge
• 金额: $ 7.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/10524092
• 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

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.

项目总结

项目成果

Use of hiPSC to explicate genomic predisposition to anthracycline-induced cardiotoxicity.

• DOI: 10.2217/pgs-2020-0104
• 发表时间: 2021-01
• 期刊: Pharmacogenomics
• 影响因子: 2.1
• 作者: Tarek Magdy;P. Burridge

An updated protocol for the cost-effective and weekend-free culture of human induced pluripotent stem cells.

• DOI: 10.1016/j.xpro.2020.100213
• 发表时间: 2021-03-19
• 期刊: STAR protocols
• 作者: Lyra-Leite DM;Fonoudi H;Gharib M;Burridge PW
• 通讯作者: Burridge PW

Prime time for doxorubicin-induced cardiotoxicity genetic testing.

阿霉素引起的心脏毒性基因检测的黄金时间。

• DOI: 10.2217/pgs-2022-0032
• 发表时间: 2022
• 期刊: Pharmacogenomics
• 影响因子: 2.1
• 作者: Magdy,Tarek;Burridge,PaulW
• 通讯作者: Burridge,PaulW

The future role of pharmacogenomics in anticancer agent-induced cardiovascular toxicity.

药物基因组学在抗癌药物引起的心血管毒性中的未来作用。

• DOI: 10.2217/pgs-2017-0177
• 发表时间: 2018
• 期刊: Pharmacogenomics
• 影响因子: 2.1
• 作者: Magdy,Tarek;Burridge,PaulW
• 通讯作者: Burridge,PaulW

Cellular model systems to study cardiovascular injury from chemotherapy.

• DOI: 10.1007/s11239-020-02299-x
• 发表时间: 2021-05
• 期刊: JOURNAL OF THROMBOSIS AND THROMBOLYSIS
• 影响因子: 4
• 作者: Fonoudi, Hananeh;Burridge, Paul W.
• 通讯作者: Burridge, Paul W.