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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Aggressive prostate cancer (PCa) with specific features is untreatable, necessitating novel therapeutic strategies.
• A unique murine model that spontaneously develops metastatic disease was utilized to study PCa progression.

Purpose of the Study:

• To identify potential therapeutic targets for aggressive prostate cancer.
• To evaluate the efficacy of combining a topoisomerase IIα (Top2a) targeting agent with an EZH2 inhibitor.

Main Methods:

• RNA-sequencing was performed on tumors from a metastatic prostate cancer mouse model.
• Differential gene expression analysis identified increased Top2a in metastatic tumors.
• In vitro and in vivo studies combined etoposide (Top2a poison) with EZH2 inhibitors (GSK126, DZNep).

Main Results:

• Topoisomerase IIα (Top2a) was significantly upregulated in metastatic tumors and correlated with aggressive human PCa.
• Combination therapy with etoposide and EZH2 inhibitors induced significant cell death in prostate cancer cell lines.
• In vivo studies demonstrated extended time to progression and increased therapeutic efficacy with combination therapy.

Conclusions:

• Increased Top2a and EZH2 expression identifies patients likely to respond to combination therapy.
• Low-dose etoposide combined with EZH2 inhibition is a promising strategy against aggressive PCa.
• This combination therapy warrants further clinical development for advanced prostate cancer treatment.