Both TOP2A and EZH2 have been independently associated with metastatic prostate cancer. This new report by Dr. Ellis and colleagues is believed to be the first to study the two together for their potential role in early detection of prostate cancer patients most likely to relapse after localized therapy.
To evaluate the potential for TOP2A and EZH2 to predict metastasis, Dr. Ellis and colleagues conducted a genome-wide analysis of seven primary prostate cancer cohorts (n=1,900), two metastatic castration-resistant prostate cancer datasets (n=290), and a prospective radical prostatectomy cohort (n=1,385), along with immunohistochemical staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients with a known outcome (n=89).
The researchers found that concurrent TOP2A and EZH2 mRNA and protein upregulation identified a group of patients with more aggressive disease and “notable overlap” of genes involved in mitotic regulation, they wrote.
In the related experiment, where they treated prostate cancer-derived murine cell lines with etoposide and EZH2 inhibitors, investigators said sensitivity to this combination treatment in the context of TOP2A and EZH2 overexpression illustrated how they are “key driving oncogenes” in the cell model.
“By targeting them, that's where we can hopefully intercept the progression to metastatic disease,” Dr. Ellis explained.
While this particular study evaluated the combination of etoposide with EZH2 inhibitors, other targeted therapies may have a potential role as an interceptor in this setting.
In particular, Dr. Ellis and colleagues pointed to the recent success of PARP inhibitors for treatment of patients with metastatic prostate cancer with defects in DNA repair genes (N Engl J Med 2015; 373:1697-708).
“Because our data highlight a subgroup of patients with increased mitotic [differentially expressed genes] and potential of increased genomic instability, PARP inhibitors may offer an alternative therapeutic opportunity,” Dr. Ellis and colleagues wrote.
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