Abstract PO-133: AGE:RAGE signaling pathway as a target in neuroendocrine prostate cancer

Abstract

Abstract Advanced Glycation End products, or AGEs are non-enzymatically attached sugar metabolites that can contribute to prostate cancer development and progression. AGEs are formed when reducing sugars interact with amino acids, proteins, lipids or nucleic acids under physiological conditions, and are categorized as either endogenous (biological-AGEs) or exogeneous (dietary-AGEs). Dietary AGEs contribute to the body’s total AGE pool, and are responsible for increased AGE accumulation, that in turn facilitates interaction with the major AGE receptor, the Receptor for Advance Glycation End products, RAGE. RAGE is a transmembrane member of the Ig superfamily of cell surface molecules and is overexpressed in a variety of tumor types, including prostate cancer. Increased AGE accumulation upregulates RAGE expression, amplifying the signaling cascade with impacts on cytokinesis. This is especially relevant, as we have shown that both AGE and RAGE are significantly elevated in tumors from AA men when compared to EA men at the same stage. De novo neuroendocrine prostate cancer (NEPC) is rare constituting only 1% of all prostate cancer cases. However, recent studies have shown that individual cells within a prostate tumor can undergo a process termed neuroendocrine differentiation to become neuroendocrine-like. Studies have shown that androgen deprivation therapy (ADT) can drive neuroendocrine differentiation leading to the development of the castrate resistant prostate cancer phenotype. These latter cancers are referred to as neuroendocrine prostate cancer (NEPC) or aggressive variant prostate cancer (AVPC). Transformation to a neuroendocrine phenotype is one proposed mechanism of resistance to contemporary AR-targeted treatments, is associated with increased tumor progression, poor prognosis, and is thought to represent ~25% of lethal prostate cancers. Due to the increased application of ADT in prostate cancer patients, neuroendocrine prostate cancer is thought to be on the rise and therefore poses a significant health problem. Our studies show that AGEs can induce neuroendocrine differentiation in AR-positive prostate adenocarcinoma cells in vitro with a concomitant loss of the AR. In addition, we observe that AGEs promote more aggressive tumor growth in both syngeneic xenograft and spontaneous mouse models in vivo. Using shRNA and pharmacological inhibitors to RAGE, we show that AGE-mediated neuroendocrine differentiation is RAGE- dependent. Results from our studies could implicate RAGE inhibitors as therapeutic treatments to reduce the increased mortality observed in AA men with prostate cancer that disproportionately have increased levels of both AGE and RAGE. Citation Format: Bradley A. Krisanits, Arabia Satterwhite, Lourdes M. Nogueira, Ashley Evans-Knowell, David P. Turner, Victoria J. Findlay, DeMarcus D. Woolfork. AGE:RAGE signaling pathway as a target in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-133.