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Abstract
Standard of care for human epidermal growth factor receptor 2 overexpression (HER2+) in breast cancer includes a combination of targeted HER2 therapy and chemotherapy. Although the combination of these therapies has significantly improved therapeutic response and overall survival, the mechanisms in which these therapies are effective in decreasing tumor burden also creates systemic toxicities within critical organs, like the brain and heart. Both targeted HER2 therapy and chemotherapy can induce decreases in cardiac function through inhibition of key cardiomyocyte survival signaling and mitochondrial dysfunction. Additionally, chemotherapy can induce neuroinflammation, through peripheral inflammation. Cardiotoxicity is traditionally monitored through echocardiogram before and throughout the duration of therapy, while cognitive impairments lack a clinical standard. Importantly, early measures of inflammation and toxicity to predict these downstream manifestations are lacking but necessary to improve patient quality of life and systemic health.
This thesis explores the use of noninvasive positron emission tomography (PET) to quantify inflammation via [18F]DPA-714, a specific biomarker for translocator protein (TSPO). TSPO has been heavily studied for its relationship in immune signaling and reactive oxygen species. We hypothesize that quantification of TSPO through PET imaging can provide early insight into inflammation within critical organs throughout the course of targeted HER2 therapy and doxorubicin, a chemotherapy commonly used to treat HER2+ breast cancer clinically. Increases to [18F]DPA-714 uptake within mice treated with doxorubicin in both the brain and the heart. Within the brain, preclinical imaging studies showed the importance of not only uptake but intensity distribution and spatial heterogeneity in characterizing neuroinflammation. Additionally, computational modeling was also able to capture the relationship of neuroinflammation and therapeutic response where predictive modeling and dose de-escalation could be utilized. Within the heart, preclinical studies demonstrated [18F]DPA-714 relationship to body weight where early imaging of [18F]DPA-714 could be used as a predictive biomarker for downstream changes in toxicity. Taken together, this thesis supports the ability for [18F]DPA-714 PET imaging to quantify early changes to both neuroinflammation and cardiac inflammation from HER2+ breast cancer therapy. Overall, this work can provide noninvasive early quantification of inflammation potentially informing therapeutic strategies to improve patient outcomes while maintaining therapeutic efficacy.