Date of Award

Summer 8-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

Harold Riethman

Committee Member

Aurora Kerscher

Committee Member

Christopher Osgood

Committee Member

Patrick Sachs

Committee Member

Michael Stacey

Abstract

Long-term Androgen deprivation therapy (ADT) is used to treat Prostate cancer (PCa) but is often met with resistance & the development of Neuroendocrine (NE) PCa which is rarer but more aggressive. Antiandrogens are a part of ADT that work to inhibit androgen receptor in PCa cells. In vitro, PCa cells under long-term antiandrogen treatment become NE-like and adopt stem-like characteristics. The disruption of androgen signaling though the use of antiandrogens impacts many cellular processes that play a major role in cancer cell proliferation such as the DNA damage repair response (DDR) and telomere dysfunction. In vivo, PCa tumors have disorganized microvasculature leading to hypoxic conditions in the tumor microenvironment which influences resistance to chemotherapy agents as well as the DDR and telomere dysfunction. Combining antiandrogens with enzymes that inhibit DNA repair (PARP inhibitors) increases effectiveness of ADT, but further research is needed to deepen the current understanding of mechanisms underlying the synthetic lethality of combining PARP inhibitors with ADT in PCa cells under hypoxic conditions that mimic the in vivo microenvironment of the prostate. The experimentation presented in this dissertation consists of culturing androgen sensitive PCa cells under long term antiandrogen treatment in standard cell culture oxygen concentrations and hypoxic conditions while investigating the response of the cells to combined treatments and assessing the impact on the DDR and telomere dysfunction. The work presented in this dissertation provides evidence that the progression of PCa cells under long term antiandrogen treatment follows a more complex trajectory under hypoxic conditions compared to standard cell culture oxygen levels and that the stages of PCa progression respond to antiandrogen and PARP inhibitor treatment in ways that impact the DDR and telomere dysfunction and that these responses impacted by hypoxia.

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In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).

DOI

10.25777/11hb-8297

ISBN

9798193214557

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