Graduation Date

Fall 12-15-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Dr. Hamid Band, M.D., Ph. D.

Abstract

Despite significant advancements in managing localized prostate cancer (PC), which have notably increased survival rates, advanced PC continues to be a leading cause of cancer- related fatalities. The discovery of new pathways that can be targeted to inhibit tumor growth in PC could pave the way for innovative treatment strategies. The disialylganglioside GD2 is an FDA-approved target for antibody therapies in neuroblastoma and has not been extensively studied in the context of PC. The work done in this thesis reveals that GD2 is present on a minor subset of PC cells in certain patients and is more prevalent in metastatic tumors. Most PC cell lines exhibit varying degrees of GD2 expression on their surface, which is significantly increased by experimental induction of lineage progression, resistance to enzalutamide, treatment with histone deacetylase inhibitors (HDACi) in the castration-resistant prostate cancer (CRPC) cell models. We observe an increase in GD2high cell fraction when PC cells are grown as tumorspheres, and this fraction is enhanced in tumorsphere-forming ability. The CRISPR- Cas9 knockout (KO) of GD3 Synthase (GD3S), the enzyme involved in GD2 biosynthesis, in GD2high CRPC cell line models significantly impairs the in vitro oncogenic traits, decreases the expression of cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT) markers and reduces growth in bone-implanted xenograft tumors. These findings underscore the potential role of GD3S and its product GD2 in driving PC tumorigenesis by maintaining CSCs suggesting that GD2 could be a potential target for advanced PC by antibody therapy or in combination with HDACi.

Comments

2023 Copyright, the authors

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