DOI

https://doi.org/10.25772/2EAQ-AM17

Defense Date

2023

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmacology & Toxicology

First Advisor

Dr. David Gewirtz

Abstract

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for new and more efficacious treatment combinations to prolong survival and offset disease progression, especially for castration-resistant disease.

While the role of antiandrogens in androgen-dependent prostate cancer is well characterized, this is not the case for the involvement of these therapies in androgen-independent disease. Furthermore, successful utilization of senolytics to target senescent cells in cancer treatment has not yet been implemented or approved for clinical use.

Initially, we evaluated the standard of care anti-androgens, enzalutamide and abiraterone, and their ability to induce growth arrest and possibly senescence in the PC3 and DU145 androgen-independent cell lines. While treatment with these antiandrogens produced a transient, growth arrest response, even in the case of supraclinical concentrations, neither drug induced significant senescence in either cell line. Despite these initially negative results, this did not rule out the possibility that a potential senolytic such as the BET degrader, ARV-825, could enhance the response to antiandrogens; therefore, we hypothesized that ARV-825 could potentially improve androgen independent castration-resistant prostate cancer’s response to enzalutamide.

While the ARV-825 failed to enhance the response to enzalutamide in combination in PC3 cells, it had a significant effect as a monotherapy. Additional studies to understand the ineffectiveness of ARV-825 in the combination proved to be challenging, with enzalutamide inducing protective autophagy being a possible explanation. The most promising direction derived from these studies is the possible use of ARV-825 as a monotherapy in androgen-independent disease. ARV-825 as a monotherapy induced a significant prolonged growth arrest in the androgen-independent cells along with decreased levels of BRD4 and c-Myc. However, the ARV-825 did not induce significant senescence or apoptosis, despite the substantial growth arrest; therefore, the nature of this growth arrest remains to be investigated. Nevertheless, ARV-825 could prove to be a clinically relevant strategy in the treatment of castration-resistant prostate cancer.

Rights

© Justin Silverman

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-2-2023

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