Master of Science (MS)
Cancer Biology (Medicine)
Date of Defense
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Fifth Committee Member
The Receptor for Advanced Glycation End-products (RAGE) is normally expressed at low levels, but is highly expressed in a variety of inflammatory states. RAGE has been implicated in pathogenic progression of cancer and various metabolic diseases, and therefore provides a potential therapeutic target in these disease states. RAGE knockout (RKO) mice are viable and display no developmental defects, suggesting therapeutic targeting of RAGE to be a viable approach. Our lab has identified two RAGE inhibitors that can be used in both in vitro and in vivo models: FPS-ZM1 (FPS) and TTP-488 (TTP). Previously, our lab has established one of these inhibitors, FPS, as a therapeutic that markedly reduced morbidity in breast cancer (BrC) and diabetes mouse models. We additionally noticed that in diabetic models, RAGE inhibition helped rescue a normal hepatic phenotype. Because of the implication of RAGE in the characteristic inflammation of BrC and metabolic diseases, as well as a growing cohort of the American population susceptible to both of these pathologies, I looked to see if RAGE presented a viable target in these disease states. First, I further optimized our drugs and characterized the effect of RAGE in syngeneic and spontaneous BrC models. Through these drug optimization experiments, I generated significant downregulation of metastasis using FPS. Secondly, I tested whether or not RAGE inhibition could affect the pathophysiological progression of diabetes, obesity, and fatty liver disease in mice. These data demonstrated a visible downregulation of hepatic lipid accumulation in drug treated mice. This work should pave the way for future studies to elucidate the role that RAGE plays in driving the inflammation of BrC and metabolic disorders, identify how each drug mechanistically inhibits RAGE signaling, and develop preclinical studies to therapeutically target RAGE in these individual and comorbid states.
RAGE; Breast Cancer; Diabetes; NAFLD; NASH; Inflammation
Willis, Owen, "Inhibition of Inflammatory RAGE Signaling in Breast Cancer and Metabolic Diseases" (2018). Open Access Theses. 722.
Available for download on Tuesday, August 04, 2020