Grant Details
Grant Number: |
5R01CA220002-05 Interpret this number |
Primary Investigator: |
Burridge, Paul |
Organization: |
Northwestern University At Chicago |
Project Title: |
Genomic Prediction of Doxorubicin-Induced Cardiotoxicity |
Fiscal Year: |
2022 |
Abstract
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.
Publications
A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors.
Authors: Sapkota Y.
, Ehrhardt M.J.
, Qin N.
, Wang Z.
, Liu Q.
, Qiu W.
, Shelton K.
, Shao Y.
, Plyler E.
, Mulder H.L.
, et al.
.
Source: Journal of the National Cancer Institute, 2022-08-08; 114(8), p. 1109-1116.
PMID: 35698272
Related Citations
Prime time for doxorubicin-induced cardiotoxicity genetic testing.
Authors: Magdy T.
, Burridge P.W.
.
Source: Pharmacogenomics, 2022 Apr; 23(6), p. 335-338.
EPub date: 2022-04-05.
PMID: 35380470
Related Citations
Identification of Drug Transporter Genomic Variants and Inhibitors That Protect Against Doxorubicin-Induced Cardiotoxicity.
Authors: Magdy T.
, Jouni M.
, Kuo H.H.
, Weddle C.J.
, Lyra-Leite D.
, Fonoudi H.
, Romero-Tejeda M.
, Gharib M.
, Javed H.
, Fajardo G.
, et al.
.
Source: Circulation, 2022-01-25; 145(4), p. 279-294.
EPub date: 2021-12-07.
PMID: 34874743
Related Citations
RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy.
Authors: Magdy T.
, Jiang Z.
, Jouni M.
, Fonoudi H.
, Lyra-Leite D.
, Jung G.
, Romero-Tejeda M.
, Kuo H.H.
, Fetterman K.A.
, Gharib M.
, et al.
.
Source: Cell stem cell, 2021-12-02; 28(12), p. 2076-2089.e7.
EPub date: 2021-09-15.
PMID: 34525346
Related Citations
Cellular model systems to study cardiovascular injury from chemotherapy.
Authors: Fonoudi H.
, Burridge P.W.
.
Source: Journal of thrombosis and thrombolysis, 2021 May; 51(4), p. 890-896.
EPub date: 2020-10-13.
PMID: 33051807
Related Citations
An updated protocol for the cost-effective and weekend-free culture of human induced pluripotent stem cells.
Authors: Lyra-Leite D.M.
, Fonoudi H.
, Gharib M.
, Burridge P.W.
.
Source: STAR protocols, 2021-03-19; 2(1), p. 100213.
EPub date: 2021-02-03.
PMID: 33786455
Related Citations
Use of hiPSC to explicate genomic predisposition to anthracycline-induced cardiotoxicity.
Authors: Magdy T.
, Burridge P.W.
.
Source: Pharmacogenomics, 2021 Jan; 22(1), p. 41-54.
EPub date: 2021-01-15.
PMID: 33448871
Related Citations
Tragacanth Gum/Chitosan Polyelectrolyte Complexes-Based Hydrogels Enriched with Xanthan Gum as Promising Materials for Buccal Application.
Authors: Potaś J.
, Szymańska E.
, Basa A.
, Hafner A.
, Winnicka K.
.
Source: Materials (Basel, Switzerland), 2020-12-27; 14(1), .
EPub date: 2020-12-27.
PMID: 33375434
Related Citations
Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report.
Authors: Singh P.
, Wang X.
, Hageman L.
, Chen Y.
, Magdy T.
, Landier W.
, Ginsberg J.P.
, Neglia J.P.
, Sklar C.A.
, Castellino S.M.
, et al.
.
Source: Cancer, 2020-09-01; 126(17), p. 4051-4058.
EPub date: 2020-05-15.
PMID: 32413235
Related Citations
Generating a Cost-Effective, Weekend-Free Chemically Defined Human Induced Pluripotent Stem Cell (hiPSC) Culture Medium.
Authors: Fonoudi H.
, Lyra-Leite D.M.
, Javed H.A.
, Burridge P.W.
.
Source: Current protocols in stem cell biology, 2020 Jun; 53(1), p. e110.
PMID: 32463953
Related Citations
Human In Vitro Models for Assessing the Genomic Basis of Chemotherapy-Induced Cardiovascular Toxicity.
Authors: Pinheiro E.A.
, Magdy T.
, Burridge P.W.
.
Source: Journal of cardiovascular translational research, 2020 Jun; 13(3), p. 377-389.
EPub date: 2020-02-20.
PMID: 32078739
Related Citations
Precise and Cost-Effective Nanopore Sequencing for Post-GWAS Fine-Mapping and Causal Variant Identification.
Authors: Magdy T.
, Kuo H.H.
, Burridge P.W.
.
Source: iScience, 2020-04-24; 23(4), p. 100971.
EPub date: 2020-03-09.
PMID: 32203907
Related Citations
Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Preclinical Cancer Drug Cardiotoxicity Testing: A Scientific Statement From the American Heart Association.
Authors: Gintant G.
, Burridge P.
, Gepstein L.
, Harding S.
, Herron T.
, Hong C.
, Jalife J.
, Wu J.C.
.
Source: Circulation research, 2019-10-25; 125(10), p. e75-e92.
EPub date: 2019-09-19.
PMID: 31533542
Related Citations
hiPSCs in cardio-oncology: deciphering the genomics.
Authors: Pinheiro E.A.
, Fetterman K.A.
, Burridge P.W.
.
Source: Cardiovascular research, 2019-04-15; 115(5), p. 935-948.
PMID: 30689737
Related Citations
Late onset heart failure after childhood chemotherapy.
Authors: Hilfiker-Kleiner D.
, Ardehali H.
, Fischmeister R.
, Burridge P.
, Hirsch E.
, Lyon A.R.
.
Source: European heart journal, 2019-03-07; 40(10), p. 798-800.
PMID: 30753420
Related Citations
Are These Cardiomyocytes? Protocol Development Reveals Impact of Sample Preparation on the Accuracy of Identifying Cardiomyocytes by Flow Cytometry.
Authors: Waas M.
, Weerasekera R.
, Kropp E.M.
, Romero-Tejeda M.
, Poon E.N.
, Boheler K.R.
, Burridge P.W.
, Gundry R.L.
.
Source: Stem cell reports, 2019-02-12; 12(2), p. 395-410.
EPub date: 2019-01-24.
PMID: 30686762
Related Citations
Unraveling Difficult Answers: From Genotype to Phenotype in Coronary Artery Disease.
Authors: Magdy T.
, Burridge P.W.
.
Source: Cell stem cell, 2019-02-07; 24(2), p. 203-205.
PMID: 30735646
Related Citations
Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems.
Authors: Magdy T.
, Schuldt A.J.T.
, Wu J.C.
, Bernstein D.
, Burridge P.W.
.
Source: Annual review of pharmacology and toxicology, 2018-01-06; 58, p. 83-103.
EPub date: 2017-10-06.
PMID: 28992430
Related Citations
The future role of pharmacogenomics in anticancer agent-induced cardiovascular toxicity.
Authors: Magdy T.
, Burridge P.W.
.
Source: Pharmacogenomics, 2018 Jan; 19(2), p. 79-82.
EPub date: 2017-12-04.
PMID: 29199515
Related Citations