Date of Award

2021

Embargo Period

4-21-2026

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

Victoria J. Findlay

Second Advisor

David P. Turner

Third Advisor

Robin Muise-Helmericks

Fourth Advisor

Harsha Karanchi

Abstract

Prostate cancer, a disease of aging, is the second leading cause of male cancer deaths in the United States and is canonically controlled by androgen expression which is treated with androgen deprivation therapy (ADT) that suppress androgen production, androgen receptor function, or both. The androgen receptor (AR) plays a critical role in cancer development, progression, and therapy response. Recurring cancer cells undergo cellular reprogramming, adopting alternative mechanisms of survival, entering an androgen receptor-independent state, and are then subcategorized as Castration Resistant Prostate Cancers (CRPC). A process known as neuroendocrine differentiation, has been shown to be upregulated in response to ADT. Neuroendocrine prostate cancers (NEPC) experience a lineage conversion from adenocarcinoma to neuroendocrine lineages via genetic and/or epigenetic dysregulation. Patients diagnosed with NEPC have poor outcomes. Advanced Glycation End Products (AGEs) are reactive metabolites that are produced through the Maillard reaction and direct oxidation of biological macromolecules and are associated with chronic pathologies, including prostate cancer. They function in part through binding to the receptor for AGE, RAGE resulting in downstream signaling events. We have previously shown that mice fed a high AGE diet have accelerated tumor growth in vivo and can induce neuroendocrine differentiation in vitro. In this study, using mouse and human models of prostate cancer representing prostate adenocarcinoma and NEPC respectively. We examined the AGE:RAGE signaling pathway in response to AGE using pharmacological inhibitors of AGE (aminoguanidine) and RAGE (TTP488), as potential therapeutic approaches to inhibit and/or reverse NED. We found that in prostate adenocarcinoma cells, AGE-mediated increases in NED were mitigated by pharmacological inhibition of both AGE and RAGE. We found that in NEPC cells inhibition of AGE or RAGE decreased the expression of neuroendocrine markers ENO2 and MYC. However, only RAGE inhibition, not AGE inhibition, was able to mitigate AGE-mediated restoration of ENO2 and MYC in this model. These data implicate these pharmacological inhibitors may have therapeutic potential for rare and lethally aggressive NEPC.

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All rights reserved. Copyright is held by the author.

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Available for download on Tuesday, April 21, 2026

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