Graduation Date

Fall 12-15-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Ming-Fong Lin

Second Advisor

Surinder K. Batra

Abstract

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, a mechanism of androgen independence. Furthermore, I investigate the role of p66Shc, a 66 kDa Src and collagen homologue oxidase, in the mechanism of PCa metastatic progression. p66Shc is elevated in clinical PCa as well as multiple PCa cell lines which correspond with advanced CR PCa. Additionally, p66Shc has been demonstrated to promote proliferation in PCa cell lines via generation of reactive oxygen species (ROS). This study is the first to demonstrate p66Shc also regulates PCa cell migration through ROS production and identifies key ROS-sensitive proteins pivotal to its mechanism. Understanding how p66Shc promotes migration may lead to the identification of alternative therapeutic targets for suppression of CR PCa metastatic activity. Overall, this study seeks to support future efforts to generate therapeutic compounds for treatment of metastatic CR PCa.

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