# Novel Strategy of PDE5-mTOR Inhibition in Attenuation of Cancer  Drug Cardiotoxicity

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $556,570

## Abstract

Project Summary
Doxorubicin (DOX) chemotherapy regimens play a prominent role in many cancer treatments. With long
term cancer survivorship, a substantial population of cancer patients remain at risk of early cardiovascular
morbidity and mortality due to DOX chemotherapy. Moreover, clinical studies have revealed that sequential
treatment of DOX with the ErbB2 inhibitor, Trastuzumab has synergistic effects in improving the control of cancer
progression and survival in breast cancer patients, and is better than either drug alone. However, the combination
therapies with the ErbB2 inhibitor coupled with DOX cause severe and aggressive form of heart failure. To
overcome this clinical problem, we propose a novel combination therapy with PDE5 inhibitor, sildenafil (Viagra)
and mTOR inhibitor, rapamycin in preventing the severe cardiotoxicity caused by DOX and DOX with sequential
use of Trastuzumab in breast cancer-bearing mice. We will evaluate the therapeutic effect of sildenafil and
rapamycin on DOX-induced cardiomyocyte death in vitro and cardiac function in vivo. In addition, we will
determine the role of inflammation in the development of cardiotoxicity by measuring the expression of TLR4,
NLRP3 and pro-inflammatory cytokines including IL-1β and IL-18. The role of cGMP-dependent protein kinase
G (PKG) activation and mTOR inhibition with associated downstream signaling pathways in protecting against
DOX-induced cardiac dysfunction will be studied. We will also investigate the effect sildenafil and rapamycin
treatment in potentiating the anti-tumor efficacy of DOX and DOX with Trastuzumab and improvement of cardiac
function in the clinically relevant mouse models of spontaneous and orthotropic breast cancer. Furthermore, we
will determine the effect of sildenafil and rapamycin in attenuation of hypertrophy in cardiac specific ErbB2
transgenic mice. Because sildenafil and rapamycin are clinically approved drugs, the proposed studies may help
in developing novel combination therapy for treatment of thousands of cancer patients experiencing the lethal
and debilitating cardiotoxic effects of DOX and Trastuzumab worldwide.

## Key facts

- **NIH application ID:** 10522272
- **Project number:** 1R01HL158951-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Anindita Das
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $556,570
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522272

## Citation

> US National Institutes of Health, RePORTER application 10522272, Novel Strategy of PDE5-mTOR Inhibition in Attenuation of Cancer  Drug Cardiotoxicity (1R01HL158951-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10522272. Licensed CC0.

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