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Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer
Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneous...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413643/ https://www.ncbi.nlm.nih.gov/pubmed/25605014 |
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author | Kirk, Jason S. Schaarschuch, Kevin Dalimov, Zafardjan Lasorsa, Elena Ku, ShengYu Ramakrishnan, Swathi Hu, Qiang Azabdaftari, Gissou Wang, Jianmin Pili, Roberto Ellis, Leigh |
author_facet | Kirk, Jason S. Schaarschuch, Kevin Dalimov, Zafardjan Lasorsa, Elena Ku, ShengYu Ramakrishnan, Swathi Hu, Qiang Azabdaftari, Gissou Wang, Jianmin Pili, Roberto Ellis, Leigh |
author_sort | Kirk, Jason S. |
collection | PubMed |
description | Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development. |
format | Online Article Text |
id | pubmed-4413643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44136432015-05-08 Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer Kirk, Jason S. Schaarschuch, Kevin Dalimov, Zafardjan Lasorsa, Elena Ku, ShengYu Ramakrishnan, Swathi Hu, Qiang Azabdaftari, Gissou Wang, Jianmin Pili, Roberto Ellis, Leigh Oncotarget Research Paper Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development. Impact Journals LLC 2014-12-26 /pmc/articles/PMC4413643/ /pubmed/25605014 Text en Copyright: © 2015 Kirk et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Kirk, Jason S. Schaarschuch, Kevin Dalimov, Zafardjan Lasorsa, Elena Ku, ShengYu Ramakrishnan, Swathi Hu, Qiang Azabdaftari, Gissou Wang, Jianmin Pili, Roberto Ellis, Leigh Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
title | Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
title_full | Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
title_fullStr | Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
title_full_unstemmed | Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
title_short | Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
title_sort | top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413643/ https://www.ncbi.nlm.nih.gov/pubmed/25605014 |
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