Chemotherapy Induced Heart Failure

The Use of REV-ERB Synthetic Agonists to Prevent Chemotherapy Induced Heart Failure 

PI: Thomas Burris 

Department: Genetics Institute 

Project start date: May 2024 - ongoing 

     Modern cancer treatments are now more effective than ever at attacking the cancer, but the problem is that healthy cells take the damage, too. One advancement is a chemotherapeutic agent called Doxorubicin but is commonly known as the “red devil chemo.” Anthracyclines like Doxorubicin are among the most efficacious chemotherapy drugs currently available and are used to treat a wide range of cancers. Their dramatic effects are two-fold, however. The severity of side effects experienced depends on the cumulative dose, with the probability of heart failure rising exponentially at a dose of 250 mg/m². Doxorubicin has been the frontline of cancer treatment for the past three decades, and its demand is on the rise; therefore, there is an urgent and unmet medical need for the development of a new drug that will treat its negative side effects. 

     The REV-ERBs are a class of nuclear hormone receptors that demonstrate a unique ability to block the biomolecular events which lead to cardiac dysfunction. For example, REV-ERB agonists prevent the shift from fatty acid to glucose oxidation after a build-up of excess pressure in the left ventricle, a metabolic response that would normally occur in chemotherapy-related heart failure (CRHF). Based on this evidence, we hypothesize that REV-ERB agonists will prevent CRHF through their blockade of pathogenic pathways.

    We will test our hypothesis with three groups of mice having a genetic background commonly used in CRHF heart failure models. One group will serve as the healthy control and will receive a sham-chemotherapy. Two experimental groups will receive Doxorubicin – one group in combination with a REV-ERB agonist and one group without. We will measure cardiac function periodically throughout the experiment using an echocardiogram and use histological techniques to compare heart tissue between groups at the end of the experiment.

    This will be an invaluable learning experience teaching me the foundational skills in animal research, histological techniques, and how to use an echocardiogram to visualize cardiovascular structures and evaluate their condition. My ultimate goal is to become a cardiothoracic surgeon-scientist, and I am currently shadowing the UF congenital heart center. This scholarship will add a new dimension to my shadowing experience and enrich my understanding of cardiovascular medicine, bringing my learning full circle.