Grant Details
Grant Number: |
3R01CA261898-03S1 Interpret this number |
Primary Investigator: |
Burridge, Paul |
Organization: |
Northwestern University At Chicago |
Project Title: |
Predicting and Preventing Chemotherapy-Inducedcardiotoxicity in African American Children |
Fiscal Year: |
2024 |
Abstract
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-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. 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 who were exposed to doxorubicin but not to
chest radiotherapy and assess their response to doxorubicin in vitro to validate our previous findings in a large
cohort of survivors 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 and chromatin accessibility quantitative
trait loci (deQTL and dcaQTL), assessing biological covariates such as doxorubicin dose, age at childhood
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 incorporating clinical risk factors and functionally assessed genetic variants above,
assess 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.
Publications
None. See parent grant details.