[18F]F-AraG as an imaging biomarker for early diagnosis and monitoring of cardiotoxicity related to doxorubicin and immune check point inhibitor therapy

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Project Summary (Abstract) Cardiovascular complications caused by cancer therapy are a major cause of morbidity and mortality in cancer patients and survivors. Cardiotoxicity of traditional cancer therapies, such as anthracyclines, as well as more selective, targeted therapies, have been well documented and underlying mechanisms of cardiac injury thoroughly studied. Cardiovascular toxicity of a newer, very promising therapy, immune checkpoint inhibitors (ICI), is not well delineated and presents a significant diagnostic and patient management challenge for cardio- oncologists. Furthermore, cardiac damage of increasingly used chemo/ICI combinatorial therapies has not been investigated to any significant extent. Due to the advantage of being noninvasive, cardiac imaging is the most commonly used technique for monitoring cardiac function during and after cancer therapy, but current methods lack molecular specificity and are unable to detect cardiotoxicity sufficiently early to allow timely intervention and amelioration of cardiovascular risks. Inability of currently used imaging methods to detect subclinical cardiac involvement represents a major bottleneck for prevention and better management of cardiac complications in cancer patients and survivors. Positron emission tomography (PET) imaging using agents that target early indicators of cardiovascular toxicity could offer a powerful and highly specific noninvasive tool for detection of subclinical cardiac toxicity associated with traditional as well as ICI cancer therapy. We propose to investigate [18F]F-AraG, a PET agent with a unique ability to evaluate a pathophysiological centerpiece of both ICI and anthracycline-related cardiotoxicity - activated T cells and mitochondrial function in cardiomyocytes - as an imaging biomarker for early diagnosis and monitoring of cardiotoxicity associated with ICI as well as chemotherapy. The immediate goal of this project is to investigate the correlation between myocardial [18F]F-AraG uptake and processes that drive ICI and anthracycline (doxorubicin) cardiotoxicity. The long-term goal is development of a highly sensitive and specific technique to guide interventions in early, subclinical phases of cardiac dysfunction. The proposed research will deliver a unique and clinic-ready imaging approach to address a key clinical problem in cardio-oncology: noninvasive detection of cardiotoxicity at an early stage to allow therapeutic interventions and reduction of cardiovascular risks. The proposed imaging technique is applicable to assessment of cardiotoxicity associated with different cancer therapies, including ICI- and combinatorial chemo/ICI approaches for which no diagnostic approach currently exists.