Graduation Date

Spring 5-10-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Grinu Mathew, Ph.D.

Second Advisor

Angie Rizzino, Ph.D.

Third Advisor

Jixin Dong, Ph.D.

Abstract

Early prostate cancer (PC) is androgen-dependent and is often treated with androgen deprivation therapy (ADT) or castration. As PC progresses to a castration-resistant state (CRPC), patients continue to receive ADT through second-generation AR antagonists like Enzalutamide. Despite therapeutic advancements, resistance to Enzalutamide poses a significant challenge in treating metastatic CRPC. Insights from multi-omics profiling in single cells have revealed complex drug resistance mechanisms and the emergence of drug-tolerant persister cells (DTPs). The receptor tyrosine kinase AXL drives DTP survival and evolution and is a drug resistance marker in various cancers. However, in PC, the relationship between AXL and drug resistance remains unclear. To address this gap, this thesis investigates the impact of ADT on Axl expression in Ar+Axl+PC cells. Data revealed a significant reduction in Axl expression following “acute ADT” (24-72 hours). Conversely, cells undergoing “chronic ADT” (>10 passages), or Enzalutamide-resistant cells, maintained Axl expression. Multi-omics studies of PCa patient samples highlight AXL gene expression exclusively in the AP-1 and YAP/TAZ-driven CRPC stem cell-like (SCL) subtype. Mechanistically, we combined ADT with small-molecule inhibitors of Hippo or AP-1 signaling pathway transcription factors to examine their impact on Axl expression. This combination treatment reduced Axl expression in Ar+Axl+ PC cells. Finally, using a syngeneic xenograft model, we aimed to evaluate the therapeutic efficacy of the GnRH antagonist Degarelix in targeting AXL-expressing CRPC cells. Our in vivo data indicated a significant reduction in tumor burden in Enzalutamide-resistant cells under Degarelix treatment, suggesting that Degarelix provides a therapeutic advantage against the CRPC-SCL subtype.

Comments

2025 Copyright, the authors

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Available for download on Friday, April 30, 2027

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