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Title: The Biological Characterization of Galeterone Analogs VNPT-178 and VNLG-74A for the Treatment of Prostate Cancer
McCarty_umaryland_0373D_10893.pdf  (5.35 MB)
Authors: McCarty, David
Advisors: Njar, Vincent
Date: 2017
Abstract: The expression of truncated androgen receptor spice-variants (AR-Vs) presents a significant clinical challenge for the treatment of advanced stages of prostate cancer and confers complete resistance to abiraterone and enzalutamide. Targeted depletion of these receptors in addition to antagonism of the androgen signaling axis has been actively evaluated as a superior treatment paradigm but has thus far been unsuccessful in clinical trials. Based on our studies of galeterone and its analogs, we believe these compounds possess a specific activity that is both independent and overlapping of their antagonism of the androgen receptor (AR). In this study, we perform basic biochemical techniques attempting to better delineate the actions of galeterone analogs VNPT-178 and VNLG-74A and identify a rational, common target for improved study of their utility against all stages of prostate cancer development. Direct comparisons of VNPT-178 and VNLG-74A to vehicle or equimolar concentrations of abiraterone and enzalutamide reveal both compounds exhibit improved antiproliferative activities in multiple prostate cancer cell models of androgen and AR dependence. VNPT-178 and VNLG-74A directly antagonize the full-length AR in LNCaP and CWR22Rv1 (22Rv1) cells while promoting the depletion of full-length and truncated receptors with dose- and time-dependency. Activation of the unfolded protein response is rapid and sustained, long preceding appreciable antagonism of the AR in 22Rv1 cells, and followed by CHOP upregulation and PARP cleavage - an effect also seen in PC-3 cells albeit with slower kinetics. Molecular docking of VNPT-178 and VNLG-74A reveals greater potential for binding the ATPase domains of BiP/Grp78 and Hsp70-1A compared to the AR's ligand-binding domain. Severe or sustained activation of the unfolded protein response can induce apoptosis. Taken together, our data suggest that galeterone analogs VNPT-178 and VNLG-74A directly modulate the substrate interactions of BiP promoting endoplasmic reticulum stress and apoptosis independent of AR antagonism. Depletion of AR proteins is possibly the result of similar activities against Hsp70. The sensitivity of 22Rv1 cells to VNPT-178- and VNLG-74A-induced apoptosis may underlie a failure of this cell model to adequately represent the clinical challenge of AR-V-expressing prostate cancers.
Subject Keywords: galeterone
Prostate--Cancer
Receptors, Androgen
Unfolded Protein Response
Description: University of Maryland, Baltimore. Molecular Medicine. Ph.D. 2017
Type: dissertation
Appears in Collections:Theses and Dissertations Graduate School
Theses and Dissertations School of Medicine

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