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TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup

Labbé, David P.; Sweeney, Christopher J.; Brown, Myles; Galbo, Phillip; Rosario, Spencer; Wadosky, Kristine M.; Ku, Sheng Yu; Sjöström, Martin LU ; Alshalalfa, Mohammed and Erho, Nicholas, et al. (2017) In Clinical Cancer Research 23(22). p.7072-7083
Abstract

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A... (More)

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches.

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Clinical Cancer Research
volume
23
issue
22
pages
12 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85034843446
  • wos:000415111900030
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-17-0413
language
English
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yes
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3a8494d8-96e9-4a9f-be88-d76b936f7281
date added to LUP
2017-12-18 10:13:53
date last changed
2018-10-03 10:51:20
@article{3a8494d8-96e9-4a9f-be88-d76b936f7281,
  abstract     = {<p>Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches.</p>},
  author       = {Labbé, David P. and Sweeney, Christopher J. and Brown, Myles and Galbo, Phillip and Rosario, Spencer and Wadosky, Kristine M. and Ku, Sheng Yu and Sjöström, Martin and Alshalalfa, Mohammed and Erho, Nicholas and Davicioni, Elai and Karnes, R. Jeffrey and Schaeffer, Edward M. and Jenkins, Robert B. and Den, Robert B. and Ross, Ashley E. and Bowden, Michaela and Huang, Ying and Gray, Kathryn P. and Feng, Felix Y. and Spratt, Daniel E. and Goodrich, David W. and Eng, Kevin H. and Ellis, Leigh},
  issn         = {1078-0432},
  language     = {eng},
  month        = {11},
  number       = {22},
  pages        = {7072--7083},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {TOP2A and EZH2 provide early detection of an aggressive prostate cancer subgroup},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-17-0413},
  volume       = {23},
  year         = {2017},
}