Date of Award

2016-01-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Marc B. Cox

Abstract

Prostate cancer (PCa) is one of the most commonly diagnosed diseases and the second leading cause of cancer deaths among men worldwide. Its growth is dependent upon androgen receptor (AR) signaling and the mainstay for treatment is hormone-ablation therapy using antiandrogens and/or androgen-deprivation therapies (ADT). Treatment of PCa with antiandrogens and/or ADT are initially effective; they act to repress the AR by directly competing with androgens for the ligand binding domain (LBD) and prevent activation of the receptor resulting in tumor regression. Unfortunately, the resistance to these treatments invariably emerges and results in a much more aggressive form of tumor that is androgen-independent termed castration-resistant prostate cancer (CRPC). Given the AR signaling axis is still active in CRPC and the heat shock protein (Hsp) 90-associated co-chaperone 52-kDa FK506-binding protein (FKBP52) plays important positive regulatory roles in AR, glucocorticoid receptor (GR), and progesterone receptor (PR) functions, FKBP52 represents a promising therapeutic candidate for treating PCa. Structure-based in silico drug screens of a virtual compound library representing lead-like molecules identified a list of 40 molecules that are predicted to bind to FKBP52. Functional screens of these hit compounds identified a lead molecule, termed GMC1, that inhibits FKBP52-enahnced AR, GR, and PR function, and impairs AR-mediated activation of PSA promoter activity. Additionally, our data show that GMC1 reduces endogenous androgen-dependent AR-regulated gene expression and PSA secretion. Finally, GMC1 impedes androgen-stimulated prostate cancer cell proliferation through destabilization of AR resulting in disruption of the hormone-binding ability of the receptor-HsP90-FKBP52 complex. Preclinical evaluations of GMC1 were performed by administering co-solvent GMC1 formulation via intratumoral injection into human xenograft mouse model. The data demonstrate promising potential in treating CRPC; tumor volumes are significant reduced compare to vehicle-treated controls. This proof-of-principle data in whole animal model further establishes FKBP52 PPIase-targeting drugs as effective therapies for PCa and warrant further preclinical development. Together, these findings demonstrate that FKBP52 is a viable target for PCa treatment and will lead to the development of more potent and effective drugs for the treatment of CRPC. Given GMC1â??s unique mechanism of action, GMC1 is likely to circumvent AR-based therapy-induced resistance mechanisms, thereby filling a major unmet need in prostate cancer therapy.

Language

en

Provenance

Received from ProQuest

File Size

151 pages

File Format

application/pdf

Rights Holder

Naihsuan C. Guy

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