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Published on: March 6, 2018
Etoposide and topoisomerase II inhibition for aggressive prostate cancer: Data from a translational study
Carlo Cattrini1, Matteo Capaia2, Francesco Boccardo3
1Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Genoa, Italy; Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Background:
Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. The activity of VP-16 was compared with that of docetaxel, enzalutamide and olaparib. The prevalence and clinical significance of TOP2 genetic and transcriptomic alterations was also explored in mCRPC.
Methods:
Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Datasets were analyzed in cBioportal.
Results:
VP-16 was active in all PCa cell lines analyzed and demonstrated increased activity in PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Maintenance of antiandrogen treatment in MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. TOP2A was found overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients' prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss.
Conclusions:
Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16.
Insights
Etoposide phosphate (VP-16) shows activity in prostate cancer (PCa) cells, with TOP2A overexpression potentially predicting response. This suggests VP-16 may benefit specific aggressive variant prostate cancer (AVPC) patient groups.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor with demonstrated activity in metastatic castration-resistant prostate cancer (mCRPC).
- Prostate cancer (PCa) exhibits diverse responses to therapies, necessitating investigation into novel treatment strategies and predictive biomarkers.
- Understanding the role of TOP2 in PCa progression and treatment sensitivity is crucial for advancing patient care.
Purpose of the Study:
- To investigate the sensitivity of various PCa cell lines to VP-16.
- To explore the relationship between VP-16 activity and TOP2 expression levels.
- To assess the clinical significance of TOP2 alterations in mCRPC.
Main Methods:
- Cell proliferation assays (crystal violet) were used to determine VP-16 activity in PCa cell lines.
- Western blot analysis was performed to assess TOP2 protein expression.
- Publicly available mCRPC datasets were analyzed for TOP2 genetic and transcriptomic alterations.
Main Results:
- VP-16 demonstrated activity across all PCa cell lines, with enhanced efficacy in PC3 and DU145 cells.
- TOP2A was overexpressed in 22Rv1, DU145, and PC3 cells, while TOP2B was overexpressed in 22Rv1 and PDB cells.
- TOP2A mRNA overexpression in mCRPC patients correlated with poorer prognosis, neuroendocrine features, lower androgen receptor (AR) scores, and RB1 loss.
Conclusions:
- Specific patient subgroups with aggressive variant prostate cancer (AVPC) may benefit from VP-16 treatment.
- TOP2A overexpression serves as a potential predictive biomarker for VP-16 response, outperforming TOP2B.
- Further research into VP-16 and TOP2A as a predictive biomarker is warranted for personalized PCa therapy.
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