Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer
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Jason S. Kirk1,3,*, Kevin Schaarschuch2,*, Zafardjan Dalimov1,3,*, Elena Lasorsa1,3, ShengYu Ku1,4, Swathi Ramakrishnan1,3, Qiang Hu5, Gissou Azabdaftari1,6, Jianmin Wang5, Roberto Pili1,7 and Leigh Ellis1,3
1 Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY
2 Department of Medicine, University of Szeged, Hungary
3 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY
4 Department of Cancer Prevention and Pathology, Roswell Park Cancer Institute, Buffalo, NY
5 Department of Bioinformatics and Statistics, Roswell Park Cancer Institute, Buffalo, NY
6 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY
7 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
* These Authors contributed equally to this work
Leigh Ellis, email:
Keywords: Top2a, etoposide, epigenetics, Ezh2, prostate cancer, therapy
Received: December 11, 2014 Accepted: December 22, 2014 Published: December 26, 2014
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.
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