# Managing Cardiac Toxicities of Cancer Therapy

> **NIH NIH R35** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $776,250

## Abstract

Project Summary
This R35 application proposes to capitalize on previous work produced by the PI over the past 11 years and to
further serve as a strong foundation for interrogating the role of sterile cardiac inflammation (inflammasomes)
in promoting the progression of heart failure caused by chemotherapy-induced cardiotoxicity and complicated
with myocardial ischemia. The overarching goal of this program is to better understand how inflammasome
formation/activation in the heart secondary to different stress signals perpetuates myocardial injury and also
dissect the contributions of different cardiac cell types during this pathophysiologic process. 1) Previous
studies from the PI’s lab have characterized the role of the inflammasome in mediating adverse cardiac
remodeling following acute myocardial infarction in preclinical models. 2) Other studies from the PI’s lab also
demonstrated that NLRP3 inflammasome inhibition reduced interstitial fibrosis and preserved systolic cardiac
function in mice exposed to doxorubicin. Evidence from the literature also supports a pathophysiologic role of
NLRP3 in mediating doxorubicin-induced cardiotoxicity. Moreover, studies from the PI’s lab and others have
shown that endogenous production of hydrogen sulfide (H2S) is essential for survival during cellular stresses,
including ischemia, and that administration of H2S donors further promotes survival. The orally-active H2S-
donor SG1002 was shown in a recent Phase I clinical trial to be safe and tolerable in heart failure patients and
also to increase blood H2S levels as well as circulating nitric oxide while attenuating BNP. We recently
demonstrated that H2S treatment attenuates ischemic and inflammatory (NLRP3 inflammasome) injury
following myocardial infarction. Accordingly, modulation of the inflammasome with H2S may represent an
important mechanism to limit inflammatory cell death and mitigate cardiomyopathy. Preliminary data
demonstrate that increases in cofilin-2 expression and its potential for phospohorylation and oxidation under
oxidative stress rises during ischemic injury, which is attenuated with H2S donors. Thus, this proposal provides
the opportunity to perform in-depth investigations on role of the cardiac inflammasome and structural proteins,
such as cofilin2, in heart failure due to chemotoxicity and also when complicated with myocardial infarction,
therefore extending our knowledge on the potential mechanism of cardiotoxicity and facilitating the design and
development of novel preventive/therapeutic modalities in the emerging field of cardio-oncology.

## Key facts

- **NIH application ID:** 10322167
- **Project number:** 5R35HL155651-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Fadi N Salloum
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $776,250
- **Award type:** 5
- **Project period:** 2021-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322167

## Citation

> US National Institutes of Health, RePORTER application 10322167, Managing Cardiac Toxicities of Cancer Therapy (5R35HL155651-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322167. Licensed CC0.

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