# Modeling Susceptibility to Chemotherapy-Induced Cardiotoxicity Using Human iPSCs

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $537,363

## Abstract

PROJECT SUMMARY
Doxorubicin is a well-established and highly effective chemotherapy drug commonly used to treat multiple cancer
types, but its use is limited by cardiotoxicity. Cardiotoxicity can range from asymptomatic reduction in left
ventricular ejection fraction to highly symptomatic heart failure (Class III to IV). Acute doxorubicin-induced
cardiotoxicity (DIC) occurs in ~11% of patients and long-term cardiotoxic side effects are observed in up to 36%
of patients. However, the underlying mechanisms of DIC remain largely unknown, hampering the development
of effective therapeutics for DIC. To that end, in this proposal we aim to use state-of-the-art approaches in
genomics and epigenetics to identify the genetic and molecular mechanisms of DIC. In Aim 1, we will generate
iPSC lines from 100 cancer patients treated with doxorubicin, 50 of whom experienced cardiotoxicity and 50 did
not. From these lines, we will perform RNA-seq and eQTL mapping to discover novel single nucleotide
polymorphisms (SNPs) responsible for DIC, and the relevant SNPs will be introduced to or deleted from non-
DIC or DIC patient iPSC lines, respectively, with the CRISPR gene editing technique. We will investigate the
functional and transcriptional changes and determine whether the identified SNP is responsible for the disease
phenotype. In Aim 2, we will perform a combination of epigenetic techniques in ATAC-seq, ChIP-seq, and IP-
mass spectrometry to identify genes regulated by topoisomerase II-beta (TOP2B), a transcriptional regulator
known to be inhibited by doxorubicin. We hypothesize that TOP2B controls genes critical for cardiomyocyte
contraction, metabolism, and homeostasis, the expression of which is disrupted upon TOP2B inhibition by
doxorubicin. Results from these experiments will reveal the specific genes regulated by TOP2B, which can be
used as potential therapeutic targets of DIC. In Aim 3, we will identify genes suitable as drug targets that are
related to DIC using the CRISPR genome screening approach. This novel technique offers a unique and cost-
efficient opportunity to systemically screen for drug target genes dysregulated by doxorubicin treatment in iPSC-
CMs. Using patient-specific iPSC-CMs, the proposed aims will allow us to elucidate for the first time the genetic
and molecular basis for DIC.

## Key facts

- **NIH application ID:** 9944656
- **Project number:** 5R01HL123968-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** THOMAS QUERTERMOUS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,363
- **Award type:** 5
- **Project period:** 2014-08-05 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944656

## Citation

> US National Institutes of Health, RePORTER application 9944656, Modeling Susceptibility to Chemotherapy-Induced Cardiotoxicity Using Human iPSCs (5R01HL123968-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944656. Licensed CC0.

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