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Cancers (Basel). 2017 Dec 6;9(12). pii: E166. doi: 10.3390/cancers9120166.

Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions.

Author information

1
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. osamasaad89@live.com.
2
Faculty of Medicine, Benha University, Benha 13518, Egypt. osamasaad89@live.com.
3
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. mnyquist@fhcrc.org.
4
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. scwheize@uw.edu.
5
School of Medicine, University of Washington, Seattle, WA 98195, USA. scwheize@uw.edu.
6
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. sbalk@bidmc.org.
7
Department of Urology, University of Washington, Seattle, WA 98195, USA. ecorey@u.washington.edu.
8
School of Medicine, University of Washington, Seattle, WA 98195, USA. splymate@uw.edu.
9
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. pnelson@fhcrc.org.
10
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. emostagh@fhcrc.org.
11
School of Medicine, University of Washington, Seattle, WA 98195, USA. emostagh@fhcrc.org.

Abstract

Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations. Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically. Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response. Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers.

KEYWORDS:

BAT; CRPC; biphasic; bipolar androgen therapy; castration resistant prostate cancer; high dose testosterone; supraphysiologic androgen

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