Overexpression of a specific pair of genes might provide early warning of prostate cancer patients’ likelihood of progressing to metastatic disease.
Researchers have found that overexpression of a specific pair of genes might provide not only early warning of which prostate cancer patients are likely to progress to metastatic disease, but also therapeutic targets for halting that progression in certain patients.
When expressed concurrently in primary human prostate cancers, the genes TOP2A and EZH2 identified patients who had a faster time to biochemical recurrence and were more susceptible to metastatic disease progression, investigators wrote online in Clinical Cancer Research (Sept. 12, 2017).
Once a susceptible patient subset is identified, it may be feasible to intervene and apply an adjuvant or neoadjuvant targeted therapeutic approach to inhibit progression to metastasis, related experimental results suggest.
In a prostate cancer mouse cell line model, increased TOP2A and EZH2 resulted in hypersensitivity to treatment with etoposide, which targets TOP2, combined with an EZH2-inhibiting compound, the investigators reported.
The findings suggest concurrent overexpression of TOP2A and EZH2 is essentially “an identifier of aggressive prostate cancer,” said researcher Leigh Ellis, PhD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston.
“As in most solid tumors, metastasis is what kills the patient,” Dr. Ellis said in an interview with Urology Times. “So if we can identify those patients that are going to metastasize before they do metastasize, then hopefully we can therapeutically intercept that, and the patient doesn't have to worry about that being an issue.”
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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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