Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Molecular and Cellular Biochemistry

First Advisor

Dr. Natasha Kyprianou

Abstract

Taxane based chemotherapy is an effective treatment for castration-resistant prostate cancer (CRPC) via stabilization of microtubules. Progression to castration-resistant prostate cancer is characterized by increased androgen receptor (AR), elevated intra-prostatic androgens and activated AR signaling despite castrate levels of androgens.

Previous studies identified that the inhibitory effect of microtubule targeting chemotherapy on AR activity was conferred by interfering with AR intracellular trafficking. The N-terminal domain (NTD) of AR was identified as a tubulin interacting domain that can be effectively targeted by the novel small molecular inhibitor, EPI. Taken together, this evidence provided the rationale that targeting AR nuclear translocation and activity via a combination of an antagonist of the AR NTD and taxane based chemotherapy may enhance the therapeutic response in CRPC. This study investigated the anti-tumor efficacy of a combination of EPI with Docetaxel chemotherapy, in cell models of CRPC, harboring AR splice variants in addition to full length AR. Our findings demonstrate there was no significant effect on androgen-mediated nuclear transport of AR variants and transcriptional activity by Docetaxel. The therapeutic response to Docetaxel was enhanced by inhibition of the NTD of AR (by EPI) through cycling of epithelial-mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) among prostate cancer epithelial cells. These results support that transient programming of EMT by the AR NTD inhibitor, potentially drives sensitivity of prostate tumors with differential distribution of AR variants to microtubule targeting chemotherapy.

The FDA-approved next-generation taxane, Cabazitaxel (CBZ) and the anti-androgen Enzalutamide (MDV3100) have demonstrated additional survival benefits for patients with advanced CRPC. The present study pursued the mechanism of therapeutic resistance to Cabazitaxel and anti-androgen treatment in vitro and in vivo models of CRPC. The findings support the ability of Cabazitaxel to target pro-mitotic kinesins, providing an insight into a new mechanism of action of this chemotherapy. Moreover, the in vivo evidence identified that Cabazitaxel chemotherapy has novel effects beyond suppressing tumor growth, by inducing prostate glandular differentiation. Our results are of translational significance in introducing a novel mechanism for cross-resistance to Cabazitaxel chemotherapy and anti-androgen therapy and a potential targeting platform to overcome such resistance in advanced CRPC.

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