Date of Award

10-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Bioanalysis

Research Advisor

Wei Li, PhD

Committee

David J. Hamilton, DMV; Bernd Meibohm, PhD; Duane D. Miller, PhD; Tiffany N. Seagroves, PhD;

Keywords

Chemotherapy; tubulin inhibitor; Colchicine binding site inhibitor; Chemoresistance; tumor organoids; Cell cycle arrest; PDAC; CRPC.

Abstract

Colchicine binding site inhibitors (CBSIs) are an emerging class of microtubule-targeting agents (MTAs) with promising potential for cancer therapy. Traditional MTAs like paclitaxel, docetaxel, and Cabazitaxel, are three FDA-approved taxanes for treating various cancers. Acquired chemoresistance and toxicities caused by chemotherapy are some of the main barriers that limit their clinical outcomes. More effective novel agents and therapeutic strategies are needed to overcome these challenges. Tremendous efforts have been made in discovering novel CBSIs and evaluating many cancer types, reporting their promising potential to treat both primary, resistant, and metastatic cancers including breast cancer, ovarian cancer, lung cancer, and melanoma. However, no CBSIs have received FDA approval to date, and limited effective discoveries have been made in advanced malignancies such as castration-resistant prostate cancer and pancreatic cancer, underscoring the need for further research in this area of drug discovery and development. This dissertation focuses on evaluating the anti-cancer efficacy of novel CBSIs developed in-house for the treatment of castration-resistant prostate cancer and pancreatic ductal adenocarcinoma. Chapter 1 outlines the rationale behind this study, emphasizing the significance of CBSIs and presenting the central hypotheses. Chapter 2 provides a detailed account of the experimental models, materials, and methodologies. Chapter 3 presents the preclinical evaluation results of the novel compound SB-216, focusing on its therapeutic potential in both in vitro and in vivo models of prostate and pancreatic cancers. Lastly, Chapter 4 discusses the broader implications of the findings and explores potential avenues for future research.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0001-9348-1058

DOI

10.21007/aetd.cghs.2024.0011

Additional Files
2024-011-Wang DOA confirmed.pdf (184 kB)
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