DOI
https://doi.org/10.25772/RZ5C-1339
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Dr. Fadi Salloum, PhD
Abstract
Doxorubicin is a widely used chemotherapeutic agent associated with dose-limiting cardiotoxicity, which can lead to long-term cardiac dysfunction and heart failure. Current cardioprotective strategies are limited, particularly in patients with aggressive cancers such as triple-negative breast cancer (TNBC), where interrupting or reducing chemotherapy intensity is clinically undesirable. This dissertation investigates the therapeutic potential of NM922, a novel small-molecule AMPK activator and mTOR inhibitor, to mitigate doxorubicin-induced cardiotoxicity without compromising antitumor efficacy.
To evaluate whether NM922 interferes with the therapeutic effects of doxorubicin in cancer, we utilized a patient-derived xenograft (PDX) model of TNBC in nude mice. Mice were treated with doxorubicin (10 or 15 mg/kg), NM922 (50 mg/kg), or both in combination. Tumor volume, mortality, and cardiac function were monitored throughout the study. While NM922 did not enhance tumor regression, it also did not impair the anticancer efficacy of doxorubicin. Importantly, NM922 significantly reduced mortality associated with higher-dose doxorubicin and preserved cardiac ejection fraction, suggesting a protective effect on cardiac tissue without compromising chemotherapy outcomes.
In a second experiment, we tested whether NM922 could restore cardiac function after the onset of doxorubicin-induced injury. Non-tumor-bearing mice were treated with 15 mg/kg doxorubicin and monitored for cardiac dysfunction. At 8 weeks post-treatment, when reduced cardiac reserve was evident, half of the doxorubicin-treated mice were randomized to receive daily NM922. Cardiac function was assessed via echocardiography and isoproterenol challenge at weeks 10 and 12. Mice treated with NM922 showed a progressive improvement in cardiac reserve, with ejection fraction returning to control levels by week 12. No significant differences in stroke volume, heart rate, or cardiac output were observed across groups, indicating a selective effect on functional reserve.
Together, these results demonstrate that NM922 can both prevent and reverse doxorubicin-induced cardiac dysfunction without attenuating its anticancer activity. These findings support the further investigation of NM922 as a cardioprotective agent in the setting of anthracycline-based chemotherapy and highlight its potential to improve long-term outcomes in patients with high-risk breast cancers.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-9-2025