# Metabolic Phenotypes of Doxorubicin-induced Cardiotoxicity in Breast Cancer

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2021 · $273,600

## Abstract

PROJECT SUMMARY/ABSTRACT
 Doxorubicin (DOX) is a highly effective chemotherapy agent that is commonly used in combination with
precision medicine to treat a wide range of cancers, including 32% of breast cancer (BC) cases. Although the
treatment has greatly increased the number of long-term cancer survivors, it has also increased the number of
patients experiencing DOX-induced cardiotoxicity (DIC). Currently, there are no validated biomarkers that can
predict the early development of DIC. Cardiac troponin released by cardiomyocytes has been used in non-clinical
studies as a marker of myocardial injury; however, it has a low specificity, and the predictive value on
cardiotoxicity is limited. Therefore, novel biomarkers of DIC are urgently needed to identify patients who are at
an increased risk, allowing early detection of the cardiotoxicity before it causes permanent cardiac damage.
Recent studies have identified new pathways that are altered in the heart during DIC, providing opportunities for
the identification of early biomarkers of cardiac toxicity. DOX is reduced by mitochondrial complex I to form a
semiquinone free radical, resulting in the oxidation of a variety of cellular molecules, including lipid peroxidation
and oxidized phospholipids. These metabolic alterations can be leveraged to develop DIC biomarkers.
Metabolomics identifies perturbations in molecular pathways due to toxicity an‐d disease and is ideally suited for
identifying early indications of DIC. Previously, our research team reported early metabolite changes in the heart
and plasma of DOX-treated mice and identified altered levels of Krebs cycle related metabolites at the lowest
cumulative dose of DOX, before troponins are released into the blood and cardiac lesions appear. Our goal is to
identify early metabolite markers of cardiotoxicity in blood that are associated with cardiac dysfunction. In
collaboration with the PI's 2 COBRE mentors, our lab is part of an ongoing clinical study of DOX-treated BC
patients. We have previously identified cohorts of patients who developed an abnormal decline in left ventricular
ejection fraction and patients who maintained normal cardiac function. We will perform untargeted metabolomics
profiling in a rat BC model of DIC to examine early plasma metabolite markers, visualize their spatial location in
the heart tissue, and then identify changes in patterns of metabolite profiles in BC patients to test the hypothesis
that DOX produces a “metabotype” consisting of oxidized lipids and metabolites that can be used as early
indicators of DIC in BC patients. Our Specific Aims are: 1) Determine the effects of DOX on cardiac function
and metabolic profiles of the plasma and heart in the MATBIII rat model of BC; and 2) Determine the dynamic
changes in plasma metabolomic profiles of BC patients that are associated with DIC. The proposed research
will have a significant impact by identifying plasma metabolic markers of early anthracycline cardiotoxic...

## Key facts

- **NIH application ID:** 10240510
- **Project number:** 5P20GM109005-07
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Ping-Ching Hsu
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $273,600
- **Award type:** 5
- **Project period:** 2015-06-24 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240510

## Citation

> US National Institutes of Health, RePORTER application 10240510, Metabolic Phenotypes of Doxorubicin-induced Cardiotoxicity in Breast Cancer (5P20GM109005-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240510. Licensed CC0.

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