Successful treatment of cancer is hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. This risk can be mitigated if the damage to the heart is detected before it becomes irreversible. Current assessment of cardiotoxicity relies upon functional measures that may not detect early myocardial damage with sensitivity or predict subsequent declines in function. New biomarkers and metrics are therefore needed to identify at-risk patients prior to therapy and to detect the onset of cardiotoxicity during or after chemotherapy. The contribution of multiple processes to progression to cardiomyopathy and heart failure, including inflammation, fibrosis, and cardiac sympathetic neuron dysfunction, that can be measured by sensitive, high resolution, and non-invasive imaging techniques such as PET, are proposed herein as a new approach to diagnosing and monitoring cardiotoxicity. Norepinephrine is the major transmitter of the sympathetic neuron system, making the norepinephrine transporter (NET) an attractive marker of sympathetic neuron function. Fibroblast activation protein alpha (FAP) is a marker of activated fibroblasts, which are thought to effect fibrosis during cardiac remodeling. Finally, Translocator Protein 18 kDa (TSPO) is a mitochondrial protein whose expression in the myocardium is sensitive to inflammation and mitochondrial dysfunction.
The aim of this project is to evaluate the predictive and/or diagnostic value of these biomarkers for detection of cancer therapy-induced cardiotoxicity. We propose to use three PET radioligands that are already in clinical use for other indications to image NET activation ([18F]]MFBG), FAP expression ([68Ga]FAPI-02), and TSPO expression ([18F]DPA-714) in a preclinical model of doxorubicin-induced cardiotoxicity. We hypothesize that [18F]MFBG signal will decrease and [68Ga]FAPI-02 and [18F]DPA-714 will increase in the myocardium following chemotherapy. To test our hypothesis, we will induce chronic cardiotoxicity in C57BL/6 mice by administration of doxorubicin (cumulative dose of 24 mg/kg), and perform weekly dynamic ?PET/CT imaging for 6 weeks. The images will be analyzed to determine maximum standardized uptake (SUVmax) and plot time-activity curves (TACs). Temporal changes in tracer uptake will be compared to concurrent measurements of cardiac function by echocardiography and morphological features of cardiotoxicity, such as hypertrophy, inflammation, and fibrosis, by immunohistochemistry. The compounds will be ranked in terms of their predictive and/or diagnostic value. We will attempt to distinguish between markers of early- and late-onset progressive cardiomyopathy, and will put forward the leading candidates for clinical imaging of chemotherapy-induced cardiotoxicity. In selecting radioligands that are already in clinical use for other indications, we are confident that successful validation of these imaging biomarkers will lead to rapid clinical translation of the approach outlined herein.
Successful treatment of cancer with anthracyclines, alone or in combination with other therapies, is hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. Current assessment of cardiotoxicity relies upon functional measures that may not detect early myocardial damage or predict subsequent declines in function with sufficient sensitivity, and new biomarkers are needed to identify at-risk patients and detect injury at an early stage before damage becomes irreversible or incurable. We propose to evaluate three PET tracers, [18F]MFBG for imaging sympathetic neuron function, [68Ga]FAPI-02 for imaging fibroblast activation, and [18F]DPA-714 for imaging inflammation, as predictive and/or diagnostic markers of progressive cardiotoxicity arising from chemotherapy.
