Profiling Prostate Cancer Therapeutic Resistance

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen rec...

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Autores principales: Wade, Cameron A., Kyprianou, Natasha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877765/
https://www.ncbi.nlm.nih.gov/pubmed/29562686
http://dx.doi.org/10.3390/ijms19030904
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author Wade, Cameron A.
Kyprianou, Natasha
author_facet Wade, Cameron A.
Kyprianou, Natasha
author_sort Wade, Cameron A.
collection PubMed
description The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery.
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spelling pubmed-58777652018-04-09 Profiling Prostate Cancer Therapeutic Resistance Wade, Cameron A. Kyprianou, Natasha Int J Mol Sci Review The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic castration resistant prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during tumor progression. A characteristic feature of EMT landscape is loss of E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting metastasis and chemoresistance. The targetable interactions between androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of biomarker discovery. MDPI 2018-03-19 /pmc/articles/PMC5877765/ /pubmed/29562686 http://dx.doi.org/10.3390/ijms19030904 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Wade, Cameron A.
Kyprianou, Natasha
Profiling Prostate Cancer Therapeutic Resistance
title Profiling Prostate Cancer Therapeutic Resistance
title_full Profiling Prostate Cancer Therapeutic Resistance
title_fullStr Profiling Prostate Cancer Therapeutic Resistance
title_full_unstemmed Profiling Prostate Cancer Therapeutic Resistance
title_short Profiling Prostate Cancer Therapeutic Resistance
title_sort profiling prostate cancer therapeutic resistance
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877765/
https://www.ncbi.nlm.nih.gov/pubmed/29562686
http://dx.doi.org/10.3390/ijms19030904
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