Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer

Jason S. Kirk, Kevin Schaarschuch, Zafardjan Dalimov, Elena Lasorsa, Sheng Yu Ku, Swathi Ramakrishnan, Qiang Hu, Gissou Azabdaftari, Jianmin Wang, Roberto Pili, Leigh Ellis

Research output: Contribution to journalArticlepeer-review

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 IIa, 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.

Original languageEnglish (US)
Pages (from-to)3136-3146
Number of pages11
JournalOncotarget
Volume6
Issue number5
StatePublished - 2015
Externally publishedYes

Keywords

  • Epigenetics
  • Etoposide
  • Ezh2
  • Prostate cancer
  • Therapy
  • Top2a

ASJC Scopus subject areas

  • Oncology

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