Author ORCID Identifier

https://orcid.org/0000-0002-1742-4825

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Toxicology and Cancer Biology

First Advisor

Dr. Natasha Kyprianou

Second Advisor

Dr. John D'Orazio

Abstract

The plasticity of prostate tumors contributes to the heterogeneity in response and acquisition of therapeutic resistance in advanced prostate cancer. Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate tumors to invade and metastasize. Our previous studies demonstrated that cabazitaxel (a 2nd generation FDA-approved taxane chemotherapy) that is used for treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET). The present study examined the effect of sequencing cabazitaxel chemotherapy mediated MET on prostate tumor re-differentiation and its impact on overcoming resistance in models of advanced prostate cancer.

The presence of DHT (1nM) decreases the efficacy of cabazitaxel treatment in vitro. Cabazitaxel treatment in vivo induced MET in LNCaP xenograft tumors as shown by increased E-cadherin and decreased N-cadherin expression. Sequencing cabazitaxel after ADT improves tumor response in androgen sensitive LNCaP models but not in CRPC 22Rv1 models. In addition, a novel AR-HSET kinesin interaction is identified as a potential androgen receptor axis therapeutic target.

Our findings provide new insights into re-programming prostate cells into an epithelial phenotype, towards re-sensitizing the cell to therapeutic targeting. There is high translational impact in therapeutic sequencing (cabazitaxel chemotherapy and ADT), an avenue towards improved therapeutic response in patients with advanced lethal CRPC.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.187

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