Overcoming Resistance in Prostate Cancer

Metastatic castrate-resistant prostate cancer (CRPC) is now regularly treated with one of two androgen-targeting therapies, abiraterone acetate, which inhibits an enzyme necessary to make testosterone, and enzalutamide, which binds and inhibits the androgen receptor. But metastatic CRPC often becomes resistant to these treatments and researchers continue to look for ways to overcome resistance and identify new tumor targets.

In a new study published in Oncotarget, researchers have identified two genes that, together, are overexpressed in prostate cancers resistant to both enzalutamide and abiraterone acetate. The genes, which have roles in DNA replication, transcription, and chromatin remodeling, have been previously linked to aggressive prostate cancer.

Leigh Ellis, PhD, professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, and colleagues, sequenced the RNA of tumors from a mouse prostate cancer model that spontaneously develops metastatic disease.  The sequencing identified two genes-topoisomerase Iiα (Top2a) and Ezh2, a histone methyltransferase-that were together overexpressed in these murine tumors.

Then, analyzing human prostate tumor sequencing data, the authors found that increased Top2a expression in prostate primary tumors was linked to more aggressive disease (P = .005). Top2a has been previously identified as a potential prognostic marker of prostate cancer prognosis. Using a data set from 113 patients at the Memorial Sloan Kettering Cancer Center in New York, the team found that Top2a mRNA levels are unregulated in 29% of patients’ tumors. Top2a overexpression correlated well with increased expression of Ezh2.

Combining the Top2 inhibitor, etoposide, and an existing Ezh2 inhibitor, GSK126, resulted in increased cell death both in murine and human prostate cell lines. Mice with prostate tumors treated with the combination therapy had a significant delay in time to disease progression compared to non-treated mice (P = .002). Treatment with either agent alone did not improve time to progression in the mouse model.

The authors, in their discussion, suggest that patients with Top2a and Ezh2 overexpression may benefit from the combined treatment of low-dose etoposide and Ezh2 inhibition. “Our data suggests that this combination therapeutic strategy is beneficial against aggressive prostate cancer, and provides strong rationale for continued clinical development,” conclude the authors.

Next, the researchers aim to understand the pathways influenced by these two genes to better understand their potential function in driving prostate cancer growth. The authors also found these genes overexpressed in other tumor types, suggesting that these biomarkers may be more broadly useful for tumors other than prostate.

“This study deepened our knowledge of the etiology of aggressive prostate cancer and will be the basis of future investigations that we hope will lead to discovery of additional biomarkers and therapeutic targets,” said Ellis in a statement.

References:

• Roswell Park Cancer Institute. (2015). Overcoming Treatment Resistance in Prostate Cancer: Roswell Park Team Proposes a New Strategy.