# Parallel Characterization of Genetic Variants in Chemotherapy-Induced Cardiotoxicity Using iPSCs

> **NIH NIH K99** · STANFORD UNIVERSITY · 2024 · $131,973

## Abstract

Project Summary
Cardiotoxicity of cancer treatments can lead to severe heart failure in cancer survivors or discontinuation of
cancer treatments. Currently, it is challenging to evaluate who is at the risk of developing cardiotoxicity prior to
cancer treatments and prevent the adverse side effects. Genome-wide association studies (GWASs) have
shown that genetic predispositions are one of the key determinants of risk susceptibility to chemotherapy-
induced cardiotoxicity. Consistently, the susceptibility to anti-cancer agents can be recapitulated by patient-
specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs), which reflect the donor
patients’ genetic makeup. The goal of this project is to identify genes and genetic variants that affect the
susceptibility to anti-cancer agents for developing cardio-protective therapies and risk assessment systems.
Although this proposal focuses on doxorubicin, which is one of the most commonly-used anti-cancer agents, the
approach described here is expandable to any other cancer treatment-induced cardiotoxicities such as those by
tyrosine kinase inhibitors and radiation therapy. First, I plan to identify genes whose inhibition or activation can
protect iPSC-CMs from doxorubicin using our iPSC-based CRISPR screening platform. The screened genes will
be causative in doxorubicin-induced cardiotoxicity (DIC) and thus promising therapeutic targets. Second, I plan
to utilize bioengineering technologies and in vivo mouse models to assess the effects of candidate therapies
more accurately than simple monolayer culture systems. Since repurposing of approved drugs can accelerate
the clinical application of the findings, I plan to test existing drugs that target the validated genes in these models.
Finally, to develop a system to evaluate the genetic susceptibility to DIC, I plan to perform parallel
characterization of many genetic variants using iPSC-based base/prime-editing screens in DIC and generate
“susceptibility scores” of individual variants that are clinically implicated in DIC. The result will help with risk
stratification of patients who receive chemotherapies.

## Key facts

- **NIH application ID:** 10897272
- **Project number:** 5K99HL166773-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Masataka Nishiga
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $131,973
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897272

## Citation

> US National Institutes of Health, RePORTER application 10897272, Parallel Characterization of Genetic Variants in Chemotherapy-Induced Cardiotoxicity Using iPSCs (5K99HL166773-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897272. Licensed CC0.

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