Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Biomarkers, Tumor / antagonists & inhibitors*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Cell Line, Tumor
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Disease-Free Survival
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Enhancer of Zeste Homolog 2 Protein
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Epigenesis, Genetic*
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Etoposide / pharmacology
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Gene Expression Regulation, Neoplastic
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Humans
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Indoles / pharmacology
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Male
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Mice, Inbred C57BL
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Poly-ADP-Ribose Binding Proteins
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Polycomb Repressive Complex 2 / antagonists & inhibitors
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / metabolism
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Precision Medicine
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Predictive Value of Tests
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology
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Pyridones / pharmacology
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RNA, Messenger / metabolism
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Time Factors
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Topoisomerase II Inhibitors / pharmacology
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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Antigens, Neoplasm
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Biomarkers, Tumor
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DNA-Binding Proteins
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GSK-2816126
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Indoles
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Poly-ADP-Ribose Binding Proteins
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Pyridones
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RNA, Messenger
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Topoisomerase II Inhibitors
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Etoposide
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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DNA Topoisomerases, Type II
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TOP2A protein, human
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Top2a protein, mouse