||5R01CA220002-02 Interpret this number
||Northwestern University At Chicago
||Genomic Prediction of Doxorubicin-Induced Cardiotoxicity
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.
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