EURURO Vol. 72 No. 3

323 476

Platinum Opinion
Bipolar Androgen Therapy: A Paradoxical Approach for the
Treatment of Castration-resistant Prostate Cancer
Michael T. Schweizer Emmanuel S. Antonarakis Samuel R. Denmeade
a Department of Medicine, Division of Oncology, University of Washington[1_TD$DIFF] and Fred Hutchinson Cancer Research Center, Seattle, WA, USA; bThe Sidney
Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Since Huggins and Hodges first described the palliative
benefits of surgical or medical castration in 1941, the
treatment of advanced prostate cancer has focused almost
exclusively on inhibiting androgen receptor (AR) signaling
(ARS) . Often overlooked, however, is the fact that Huggins
also postulated that treatment with excess androgens, a
strategy he called ‘‘hormone interference’’, could also
produce a therapeutic benefit The seemingly paradoxical
ability of supraphysiologic androgen levels to inhibit
prostate cancer growth has been demonstrated in multiple
in vitro and in vivo studies. In addition, a number of case
series recounting the benefits of testosterone (T) supple-
mentation in prostate cancer patients have peppered the
literature for more than half a century . More recently,
preclinical studies have shed light on the mechanisms
underlying the antitumor effects of androgens These
findings have renewed our interest in exploring high-dose T
as a therapeutic strategy for men with advanced prostate
cancer, and have provided the impetus for the development
of a series of prospective studies testing intermittent high-
dose T in the clinic, a therapeutic strategy we have termed
bipolar androgen therapy (BAT).
As prostate cancer cells transition from a hormone-
sensitive to castration-resistant state, one of the most
frequently observed events is adaptive upregulation of AR
expression . It has been shown that AR upregulation
drives resistance to ARS inhibition. However, such upregu-
lation may also create a therapeutic liability. We and
others have observed that a number of AR-overexpressing
cell lines display blunted cell growth and cell death
when exposed to supraphysiologic androgen levels
. Thus, at supraphysiologic levels, T is able to
exert a pharmaceutical effect in AR-overexpressing prostate
cancer cells that results in inhibition of prostate cancer
growth. Cells that adaptively downregulate AR expression
or that have low basal levels of AR may also be killed when T
levels are allowed to rapidly drop back to castrate levels
over a cycle of BAT.
Studies exploring the mechanisms behind the paradoxi-
cal antitumor effects of supraphysiologic androgen levels
have demonstrated that in high-AR cell lines, rapid
transition from a castrate to a high-androgen environment
induces transient double-strand DNA (dsDNA) breaks that
can produce gene rearrangements such as TMPRSS2-ERG
. More recently, a clinical case report described an
extreme response to BAT in a patient with germline
mutations in the homologous recombination genes BRCA2
and ATM .
Another potential mechanism underlying the antitumor
effects of high-dose T is related to the role that AR plays as a
DNA licensing factor in prostate cancer cells . During the
cell cycle, nuclear AR binds to origins of replication and
participates in the formation of prereplicative complexes
that allow DNA replication to proceed. Under normal
conditions, AR is degraded from origins of replication and is
absent during mitosis. Under high-androgen conditions,
however, sufficient ligand-bound nuclear AR persists during
mitosis, and probably interferes with DNA relicensing,
leading to cell death in daughter cells.
Finally, differences in the AR transcriptome are present
when high-AR cell lines are exposed to either high or
low androgen concentrations . Under high-androgen
ava ilable at
journal homepage:
* Corresponding author. [2_TD$DIFF]Seattle [3_TD$DIFF]Cancer [4_TD$DIFF]Care Alliance, 825 Eastlake Ave E, Seattle, WA 98109, USA. Tel. +1 206 2887595; Fax: +1 206 2882042.
E-mail addresses: (M.T. Schweizer).
** Corresponding author. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Tel. +1 410 9558875; Fax: +1 410 6148397.
E-mail address: (S.R. Denmeade).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.