Glycans and Glycoconjugates as Biomarkers and Therapeutic Targets for Therapy-Resistant Prostate Cancer

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2023

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Abstract

Prostate Cancer (PCa) is the most common non-cutaneous malignancy and second leading cause of cancer-related mortality in men. Although most men are diagnosed with early-stage disease which is curable through prostatectomy or local radiation, a subset of men develop biochemically recurrent or metastatic disease requiring the use of hormonal therapy. Despite being initially successful, all men treated with hormonal therapy will eventually develop castration-resistant PCa (CRPC) in which the tumor cells are able to actively proliferate and metastasize despite continued androgen receptor (AR) inhibition. Furthermore, ~17-20% of CRPC tumors recur as small cell neuroendocrine carcinoma (SCNC), consisting entirely of AR-negative neuroendocrine (NE) cells which normally only represent 1% of the tumor cell population in the common, adenocarcinoma setting. Based on these observations, there remains an urgent need to discover important molecules in advanced form of PCa that can provide biological insight into CRPC and SCNC, serve as biomarkers for disease subsets, as well as have therapeutic potential. Although many authors have studied changes in the levels of many biomolecules, glycans and glycoconjugates have remained severely understudied due to the complexity of these structures as well as technological limitations. Therefore, the work in this dissertation has explored these structures specifically in the pursuit of developing novel biomarkers and therapeutic targets for advanced forms of PCa and hormone therapy-resistant tumor cells. Furthermore, the information from these studies provides novel information on how tumor glycosylation evolves throughout the evolution of PCa offering new biological insight. Chapter 1 provides a brief overview of PCa, including mechanisms of resistance to hormonal therapy as well as the concept of cellular heterogeneity and its role in disease progression and treatment resistance. Chapter 2 reviews classical and modern studies that have focused on glycans and glycoconjugates and their important role in the progression of PCa. Furthermore, Chapter 2 emphasizes the potential role these structures may serve as both diagnostic and prognostic biomarkers in the context of both tissue and liquid biopsy specimens. Chapter 3 demonstrates the expression of an oncofetal heparan-sulfate proteoglycan, Glypican-3 (GPC3), in NE cells of human PCa, including the highly lethal SCNC variant. Furthermore, Chapter 3 explores the function of GPC3 in NE tumor cells of human PCa as well as its potential molecular mechanism. Chapter 4 explores the utilization of N-glycan imaging mass spectrometry (IMS) to discover N-glycan markers of various stages of PCa progression, including the hormone-naïve, hormonally-treated, hormone-refractory, and NE subsets. Furthermore, the use of several of these discovered N-glycan structures as potential therapeutic targets is discussed as an important future direction to our work. Finally, Chapter 5 provides an outlook on the future exploitation of glycans and glycoconjugates as both biomarkers and therapeutic targets to improve the ability to diagnose clinically-relevant tumors as well as improve treatment options for patients with advanced disease.

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Butler, William (2023). Glycans and Glycoconjugates as Biomarkers and Therapeutic Targets for Therapy-Resistant Prostate Cancer. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/27590.

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