View
5
Download
0
Category
Preview:
Citation preview
Endocrine-RelatedCancer
Thematic ReviewC Helsen et al. Role of AR antagonists in
treatment of PCa21 :4 T105–T118
Androgen receptor antagonists forprostate cancer therapy
Christine Helsen1, Thomas Van den Broeck1,2, Arnout Voet3, Stefan Prekovic1,
Hendrik Van Poppel2, Steven Joniau2 and Frank Claessens1
1Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine,
Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium2Urology, Department of Development and Regeneration, University Hospitals Leuven, Herestraat 49,
3000 Leuven, Belgium3Laboratory for Structural Bioinformatics, Center for Life Science Technologies, RIKEN, Yokohama, Japan
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Published by Bioscientifica Ltd.
Printed in Great Britain
This paper is one of 12 papers that form paAndrogens and the AR in Breast and Prostatewere Wayne Tilley and Frank Claessens. F Clof this paper, on which he is listed as an au
Downloa
Correspondence
should be addressed
to F Claessens
frank.claessens@med.
kuleuven.be
Abstract
Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa).
Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or
antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting
evidence concerning the role of AR antagonists in the management of PCa. In the
castration-resistant settings of PCa, docetaxel has been the only treatment option for
decades. With recent evidence that castration-resistant PCa is far from AR-independent,
there has been an increasing interest in developing new AR antagonists. This review gives
a concise overview of the clinically available antiandrogens and the experimental AR
antagonists that tackle androgen action with a different approach.
Key Words
" androgen receptorantagonist
" antiandrogen
" enzalutamide
" bicalutamide
" abiraterone
" prostate cancer
rt oCa
aesthoded
Endocrine-Related Cancer
(2014) 21, T105–T118
Introduction
Prostate cancer (PCa) remains a major healthcare problem
and it is expected that the prevalence will only increase
due to aging of the population. In 2013, it is estimated that
PCa will account for 28% of all cancers in the USA with
29 720 expected PCa-related deaths (Siegel et al. 2013).
Epidemiological studies from Europe show comparable
data with an estimated incidence of 416 700 new PCa cases
in 2012, representing 22.8% of cancer diagnoses in men.
In total, 92 200 PCa-specific deaths are expected, making
it one of the three cancers men are most likely to die
from, with a mortality rate of 9.5% (Ferlay et al. 2013).
Due to its heterogeneity, the treatment of PCa has
been shown to be an important challenge, for which
careful selection of the most suitable treatment regimen
is required (Fig. 1).
Currently, therapy selection is based on clinical
staging (including TNM staging, Gleason scoring, and
prostate specific antigen (PSA) levels) and patients’ overall
health status. Low-risk, localized PCa is generally managed
by active surveillance. For intermediate- and especially
high-risk disease, more invasive therapy is required, for
which surgery or radiotherapy are currently the standard
treatment options whether or not within the context of a
multimodal approach. In the metastatic setting, androgen
deprivation therapy (ADT) is the mainstay treatment,
targeting androgen receptor (AR) signaling. The first
therapies, aimed at blocking AR activity, were already
being used in the 1940s by Huggins (1942). He proposed
castration and high doses of estrogens to create an
androgen-deprived state of the tumor. This revolutionary
method was refined during the years and has led to the use
of luteinizing hormone-releasing hormone (LHRH) ago-
nists that interfere with the hypothalamic–pituitary–testis
axis, leading to androgen deprivation. This initially leads
f a thematic review section onncer. The Guest Editors for this sectionsens was not involved in the handlingr. from Bioscientifica.com at 08/01/2021 08:15:59AM
via free access
LHRH-antagonists
Localized
Completeandrogenblockade
Radiotherapy+
HT
Metastatic prostate cancer
Dis
ease
pro
gres
sion
Organ-confined
Extra-capsular
Metastases
Activesurveillance
Radicalprostatectomy
Radiotherapy
Radicalprostatectomy
Castration-resistant
LHRH-agonists
Addition of a non-steroidalanti-androgen (NSAA)
Docetaxel-resistant
Orchiectomy
Withdrawal of NSAA
Abiraterone Sipuleucel T Docetaxel
AbirateroneEnz
(MDV3100) Cabazitaxel Alpharadin
Castration-resistant
Docetaxel-resistant
Locally advanced
Figure 1
Overview of prostate cancer therapy. This scheme gives the therapeutic
options assigned to each stage of prostate cancer disease. Based on
tumor characteristics, patients’ health status, biological age, and
personal preference, the optimal therapeutic regimen can be chosen.
Treatments with a dotted frame are not considered as standard
therapy according to the EAU guidelines. HT, hormone therapy; NSAA,
non-steroidal antiandrogen. Adapted from Higano & Crawford (2011)
and Massard & Fizazi (2011).
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T106
to tumor regression, but eventually the tumor adapts to
the low androgen levels by developing an alternative way
of activating AR or by bypassing AR (Higano & Crawford
2011, Massard & Fizazi 2011). This stage of the disease is
referred to as castration-resistant PCa (CRPC).
In the castration-resistant setting, docetaxel has been
the only treatment option that could prolong life for
decades. The recent understanding that the AR remains an
important target, even in the castration-resistant setting,
has led to the development of a plethora of treatment
options targeting the AR.
The goal of this review is to give an insight into
the available therapeutic options for the treatment of
metastatic PCa, directly or indirectly targeting the AR.
Secondly, we will review the preclinical development of
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
a number of novel AR antagonists. Other promising non-
AR-targeted therapies such as cabazitaxel (de Bono et al.
2010), sipuleucel-T (Higano et al. 2009), alpharadin
(Harrison et al. 2013), and tasquinimod (Armstrong et al.
2013) are currently under development but are not within
the scope of this review.
AR-targeted therapies
As androgens have a pivotal role in the development of the
prostate gland and prostate carcinogenesis, the AR is the
fundamental target of systemic therapy for PCa (Taplin &
Balk 2004). The AR is a ligand-dependent transcription
factor that is activated when androgens are present (Helsen
et al. 2012a). In response to androgen binding, it can initiate
expression of genes that contain response elements, which
are recognized by the AR (Denayer et al. 2010). Indeed, in
prostate cells, the AR controls the balance between cell
differentiation and proliferation. In normal prostate tissue,
the scale is tipped toward differentiation, while during
progression of PCa from early to advanced cancer the scale
gradually tips in favor of proliferation. This shift is
accompanied by a downregulation of genes that support
differentiation and upregulation of genes that promote
proliferation (Hendriksen et al. 2006, Marques et al. 2011).
Thus, the uncontrolled cell growth that is associated with
PCa is reflected by a shift of the transcriptional program of
AR toward a proliferative gene set (Wang et al. 2009). It is
therefore crucial to inhibit androgen signaling either by
depriving the tumor from androgens or by blocking the
receptor activity. AR activity can be enhanced not only by
steroids produced in the testis and adrenal glands but
also by androgens that were synthesized by the tumor itself
(Montgomery et al. 2008). In that way, the tumor supports
its own uncontrolled AR activity leading to CRPC.
Androgen deprivation therapy
Inhibition of testicular androgen synthesis ADT
leads to a systemic decrease in the level of circulating
androgens resulting in an androgen-depleted environ-
ment that prevents activation of the AR (Fig. 2). ADT,
achieved by chemical or surgical castration, still is the
mainstay of treatment for patients with metastatic PCa.
Due to convincing evidence showing comparable efficacy,
surgical castration is generally replaced by chemical
castration in the Western world (Soloway et al. 1991,
Vogelzang et al. 1995, Seidenfeld et al. 2000).
Chemical castration is achieved by blocking the
hypothalamic–pituitary–testis feedback system with
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
CYP17A1 inhibitor
AR
Inactive AR
Function
DHT
CoR
AF1
Prostate
TestosteroneDHEA
Pituitary gland
Adrenal glands Testis
ACTH FSHLH
Hypothalamus
LHRH
CYP17A1 inhibitor
Neg
ativ
e fe
edba
ck LHRH
antagonistLHRH agonist
Figure 2
Androgen deprivation therapy. Depriving the tumor from androgens is one
strategy to tackle uncontrolled androgen signaling by the AR. LHRH
analogues, both agonists and antagonists, are able to inhibit the synthesis
of testosterone in the testis and of DHEA in the adrenal glands by affecting
the hypothalamic–pituitary–gonadal/adrenal axis. CYP17A1 inhibitors
cause androgen deprivation by inhibiting the intracellular biosynthesis of
androgens in the testis and adrenals starting from cholesterol. Besides
reduced testosterone, DHT, and DHEA levels, some CYP17A1 inhibitors
(e.g., abiraterone and TOK-001) are also able to directly bind to the
androgen receptor (AR) and block its activity as a ligand-dependent
transcription factor. LHRH, luteinizing hormone-releasing hormone; FSH,
follicle-stimulating hormone; LH, luteinizing hormone; ACTH, adrenocor-
ticotropic hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestos-
terone; AF1, activation function 1; CoR, corepressor complexes.
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T107
LHRH analogues (Fig. 2). Currently, the available LHRH
agonists are leuprolide, goserelin, triptorelin, and histre-
lin, which need to be administered, monthly to yearly, by
injection or implantation. There is an initial release of
luteinizing hormone, causing a downregulation of LHRH
receptors at the hypothalamus, disrupting the hypo-
thalamic–pituitary–testicular axis and therefore reducing
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
testosterone production (Schally et al. 1992). Due to the
initial release of luteinizing hormone (increase by up to
tenfold), there is an initial rise in testosterone levels
(approximately twofold), occurring during the initial 72 h
of treatment, which leads to a transient increase in PSA
levels (Thompson 2001). Testosterone levels are being
suppressed at 10–20 days from administration, however,
at a lower efficacy compared with orchidectomy, as a
significant number of patients treated with the LHRH
agonists fail to reach castrate levels of testosterone (Wex
et al. 2013).
It has been suggested that this ‘biochemical flare’,
occurring in 4–63% of patients, could cause clinical ‘flares
of disease’, with reports of increased pain from bone
metastases, spinal cord compression, pathological frac-
tures, bladder outlet obstruction, and even death (Bubley
2001, Heidenreich et al. 2011). Besides the initial flare,
miniflares are observed within 12 h after the second or
subsequent administration of the LHRH agonist (Sarosdy
et al. 1999, Sharifi & Browneller 2002). To prevent these
flares, antiandrogens (see below) are being combined with
LHRH agonistic treatment, before and during the first
weeks, to reach a total androgen blockade. While the
antiandrogens will block the action of testosterone and
adrenal androgens on the AR, they will not inhibit the
hormonal surge and some of the potentially harmful
effects that it produces (Brawer 2001).
To circumvent the flares, LHRH antagonists have been
developed, resulting in an equally effective, but more
rapid chemical castration as LHRH agonists (Van Poppel
et al. 2008, Crawford et al. 2011, Garnick & Mottet 2012,
Ozono et al. 2012). Moreover, the LHRH antagonists do
not have increased risk for cardiovascular diseases as is the
case for LHRH agonists (Levine et al. 2010).
Despite the lack of evidence on the contribution of
antiandrogens, the current EAU Guidelines recommend
ADT therapy in all (symptomatic and asymptomatic)
metastatic patients combined with short-term adminis-
tration of antiandrogen therapy to reduce the risk of the
‘flare’ phenomenon in patients receiving LHRH agonists.
They emphasize that, especially in patients at high risk of
‘clinical flare’, LHRH agonists should not be administered
as monotherapy, even though there is no evidence of
long-term effects (Heidenreich et al. 2011).
Inhibition of adrenal and intracellular androgen
synthesis Despite the initial good response to ADT, PCa
progresses toward a castration-resistant stage after a median
time of 2–3 years (Knudsen & Kelly 2012). This means that
the tumor has adapted to survive the castrate levels of
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T108
androgens or the presence of antiandrogens. Frequently,
AR signaling has been restored not only by an upregulation
of the AR, by mutation of the AR, by an imbalance of
AR co-regulatory proteins but also by the synthesis of
androgens in the tumor cells itself (Taplin & Balk 2004).
Several compounds, such as ketoconazole and abir-
aterone, are able to inhibit the intracellular biosynthesis
of androgens (CYP17A1) and thereby prevent activation
of the AR (Attard et al. 2009; Fig. 2). Compared with
ketoconazole, abiraterone acetate is a potent, selective,
and safe drug. It inhibits the androgen synthesis not only
in the testis but also in the adrenal glands and the prostate
(Attard et al. 2009). Ketoconazole and abiraterone have
to be administered together with prednisone to avoid
symptoms of mineralocorticoid excess, caused by an
excess of ACTH secretion (Danila et al. 2010).
Abiraterone acetate Abiraterone acetate was developed to
manage metastatic PCa, progressing after chemotherapy.
One of the observed adaptive mechanisms in PCa cells
CPA
Abirat
DHT
TAK700
H
H H
H
OH
O
CYP17A1 inhibitor
NH
N
N
O
OH
CI
H
H
H
O
H
OH
Figure 3
Steroidal antiandrogens and CYP17 inhibitors. The CYP17 inhibitors with a stero
AR. DHT, dihydrotestosterone; CPA, cyproterone acetate; MPA, medroxyproges
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
resulting in castration resistance is an increase of the
intracellular androgen levels (Montgomery et al. 2008).
CYP17A1, which is an enzyme involved in the androgen
biosynthesis pathway, is specifically inhibited by abirater-
one. By suppressing testosterone synthesis in the adrenals
and intratumorally, administration of abiraterone results
in decreased intraprostatic testosterone levels.
After the efficacy had been proved in clinical trials
on both chemotreated and chemonaive mCRPC patients
(de Bono et al. 2011, Ryan et al. 2013), the drug was
approved by the FDA and EMA for use in patients with
mCRPC. Recently, Richards et al. (2012) demonstrated that
part of the mechanism of action of abiraterone (steroidal)
can be attributed to AR binding and inhibition (Fig. 2).
Novel CYP17A1 inhibitors Other CYP17A1 inhibitors are under
development (Vasaitis et al. 2008, Yamaoka et al. 2012;
Fig. 3). Indeed, abiraterone is an inhibitor of both the
C17,20-lyase activity and the 17a-hydroxylase activity of
CYP17A1 and inhibition of the latter causes symptoms
Steroidal antiandrogens
erone
MPA
TOK-001
H
O
O
O
H
H
N
H
H H
O OO
H
O
H H
N
N
H
OH
idal structure also display antiandrogenic effects by binding directly to the
terone acetate.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
DHT
AR
Active AR
CoA
FunctionAF1
Bic
AR
DHT
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T109
of mineralocorticoid excess. Therefore, compounds with
higher specificity against the C17,20-lyase activity of
CYP17A1 have been developed to prevent the need for
prednisone. TAK700, a non-steroidal CYP17A1 inhibitor,
is an example of more selective CYP17A1 inhibitor;
however, the phase 3 clinical trial with TAK700 has
ended preliminary because of the observation that
TAK700 plus prednisone would not likely meet the
primary endpoint of improved overall survival compared
with placebo plus prednisone. For TOK-001, it is known
that it is not only a CYP17 inhibitor, but also a competitive
AR antagonist that results in the downregulation of the
AR (Vasaitis et al. 2008, Bruno et al. 2011).
Inactive AR
Function
CoR
AF1
Enz
AR
Inactive AR
Function
DHT
CoR
AF1
Figure 4
Mechanism of action of AR antagonists. After binding to the ligand-
binding pocket of AR and nuclear translocation of AR, dihydrotestosterone
(DHT) is able to induce the formation of a coactivator-binding platform,
called AF1, which leads to the recruitment of coactivators (CoA). These
coactivators will induce the formation of an active transcriptional complex
containing RNA polymerase that leads to transcription of androgen-
regulated genes. AR antagonists can interfere with all of these required
events for activation of AR gene expression by an androgen. Bicalutamide
(bic) binds to the ligand-binding pocket of AR but fails to induce the correct
conformational change. The platform that is formed cannot recruit
coactivators, but corepressors (CoR) leading to an inactive AR–DNA
complex. Enzalutamide (Enz) has a similar mechanism of action as bic,
but can prevent nuclear translocation of the AR and the binding of AR
to DNA as well, making it a stronger AR antagonist.
Antiandrogens
AR antagonists or antiandrogens prevent androgens from
carrying out their biological activity by directly binding
and blocking the AR LBD, and by inducing repressive
activity (Fig. 4).
The current roles of antiandrogen therapy are limited
to preventing the flare-up of LHRH-agonistic therapies
(see above) and usage in combination with LHRH-
agonistic or -antagonistic therapy to achieve complete
androgen blockade (Fig. 1).
Despite the fact that chemical or surgical castration
reduces 95% of testosterone levels, an intraprostatic
androgen stimulus is still present as a result of circulating
androgens and androgen precursors of adrenal origin.
Adding an antiandrogen to castration blocks the action of
these adrenal androgens, resulting in complete androgen
blockade. However, as the clinical advantage of this
combined treatment is still questionable, the current
EAU guidelines do not recommend this as standard
treatment (Heidenreich et al. 2011).
In the next section, we will discuss the current
evidence on the role of (steroidal and non-steroidal)
antiandrogens in treating advanced PCa.
Steroidal antiandrogens In analogy with the
structure of androgens, the first antiandrogens contained
a steroidal skeleton to ensure binding to the receptor
(Fig. 3). Several steroidal antiandrogens (cyproterone
acetate (CPA), megestrol acetate, and medroxyprogesterone
acetate) were initially used for obtaining maximal
androgen blockade in patients; however, severe
drawbacks such as hepatotoxicity, interference with libido
and potency, cardiovascular side effects, and low efficacy
have limited their clinical use (Jacobi et al. 1980,
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
Pavone-Macaluso et al. 1986, 1989, Moffat 1990, Patel
et al. 1990, Dawson et al. 2000, Schroder et al. 2004).
The side effects that occur for these drugs are related
to their effects on other steroid receptors such as the
progesterone receptor and the glucocorticoid receptor, for
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T110
which they are (weak/partial) agonists (Pridjian et al. 1987,
Schroder 1993). Interference with libido and potency is the
result of their antigonadotropic effects leading to reduced
secretion of LH and follicle-stimulating hormone (FSH) and
as a consequence decreased plasma levels of T and E. Unlike
the steroidal antiandrogens, flutamide (flut) increases T
and E levels which could lead to gynecomastia (Schroder
1993). In concert with LHRH treatment, the steroidal
antiandrogens seem to reduce gynecomastia and hot
flushes. The effectiveness of the LHRH therapy, however,
cannot be increased as was shown in a prospective,
randomized study comparing goserelin acetate vs CPA vs
a combination of the two, and this study concluded that
CPA as monotherapy was inferior and the combined
treatment was not superior to goserelin acetate alone
(Thorpe et al. 1996). With regard to reducing hot flushes,
Irani et al. (2010) performed a randomized double-blind
trial, comparing efficacies of these drugs, concluding that
medroxyprogesterone acetate could be considered as the
standard treatment for hot flushes.
Non-steroidal antiandrogens Non-steroidal antian-
drogens (NSAAs) were first introduced in 1989 in clinical
practice as treatment for advanced and metastatic PCa.
Currently, they are mainly used in combination with
LHRH agonists in preventing clinical ‘flare-up’ and in
combination with LHRH agonists/antagonists to achieve
‘complete androgen blockade’ (see above). Available drugs
are the first-generation antiandrogens flut, bicalutamide
(bic), and nilutamide (nil), and the second-generation
compound enzalutamide (enz) (previously known as
MDV3100) (Fig. 5). They antagonize the actions of
androgens at the receptor level and thereby inhibit
tumor growth. The first-generation antiandrogens bic
and nil were derived from flut and thus have a similar
non-steroidal, chemical structure (Fig. 5). The non-
steroidal structure avoids the typical constraints associ-
ated with the previous steroidal antiandrogens. Of them,
bic is the best tolerated and most stable antiandrogen
currently used in clinical practice. It has a half-life of seven
days compared with 6–8 h for flut and 2 days for nil which
allows once-a-day dosing (McLeod 1997). The efficacy of
bic in clinical trials was reported to be at least equivalent
to the efficacy of flut (Schellhammer et al. 1996) and it is
better tolerated in terms of diarrhea, a common adverse
effect in flut-treated patients (Sarosdy 1999). No beneficial
effects were observed for nil over flut and nil has
the least favorable safety profile (Sarosdy 1999). While
peripheral selectivity was observed in intact rats due to a
low passage across the blood–brain barrier (Furr 1996), this
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
was not the case in men with advanced PCa. Their serum
LH and serum T levels were significantly increased due to
bic therapy (Mahler & Denis 1990).
Enzalutamide was first introduced in 2009 as a
second-generation antiandrogen with several advantages
over bic (Tran et al. 2009). In contrast to the ‘classical
antiandrogens’, enz does not only block androgen
binding, but it also inhibits translocation of the AR to
the nucleus and impairs AR binding to DNA (Tran et al.
2009). It has been approved by the FDA and EMA for
treating patients with chemo-resistant CRPC (Ning et al.
2013). Further structural optimization for inhibition of
proliferation, pharmacokinetics, and in vivo efficacy
resulted in the development of a compound called ARN-
509 (Fig. 5). It has a higher efficacy than enz, as 30 mg/kg
per day has the same therapeutic effect as 100 mg/kg per
day enz (Clegg et al. 2012). Moreover, due to the lower
required dosage of ARN-509, it has a lower tendency to
induce seizures, a typical side effect of antiandrogens from
the bic class (Foster et al. 2011).
Clinical use Several studies have been conducted to
determine the efficacy and to assess whether NSAAs in
monotherapy have an advantage over LHRH analogues
regarding side effects such as erectile dysfunction, loss of
libido, fatigue, etc. Both the first- and second-generation
NSAAs demonstrate an identical off-target on GABAA
receptors in the brain, leading to seizures (Foster et al.
2011). In light of this, ARN-509 has been developed, which
has a reduced passage through the blood–brain barrier.
We will briefly discuss the clinical use of the first- and
second-generation antiandrogens.
Flutamide Flut was the first NSAA available for clinical use,
approved by the FDA in 1989. It is indicated to use in
combination with LHRH agonists for the management
of locally confined/advanced and metastatic PCa.
Its role as a monotherapeutic agent is still unclear, with
only one randomized controlled trial (RCT) published,
comparing the therapeutic efficacy of flut with surgical
castration in patients with metastatic PCa. However, the
results remained inconclusive on its efficacy (Boccon-
Gibod et al. 1997). Furthermore, the EORTC group could
not show a difference in outcome between flut and CPA
either (Schroder et al. 2004). The same EORTC trial 30892
showed that only 20% of men treated with flut remained
sexually active for 7 years (Schroder et al. 2004). Due to
the poor evidence for its efficacy and its side effects on
sexual activity in men, flut is currently not indicated as
a monotherapeutic drug in patients with metastatic PCa.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
N
O
N
NH
S O
F
NN
F
F F
Non-steroidal antiandrogens
First-generation
HN
O2N
F
F F
Nilutamide
Second-generation
Flutamide Enzalutamide
Bicalutamide ARN-509
N NH
O
OCH3
CH3
O2N
F
F F
HN
O
OHO O
S
FN
F
F F
O
N
O
N
NH
S O
F
N
F
F F
Figure 5
Non-steroidal antiandrogens. Both the first- and second-generation
antiandrogens that are currently being used in clinical practice share a
structural motif consisting of an anilide substituted with a trifluoromethyl
group in meta-position and a nitro- or cyano-group in para-position. In
nilutamide, enzalutamide, and ARN-509, the amide of the anilide is a part
of (thio)hydantoin.
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T111
Bicalutamide Bic is currently the most investigated and most
widespread NSAA in clinical practice, with recommended
doses of 50 mg/day in complete androgen blockage and
150 mg/day for monotherapy. The latter has been inves-
tigated most extensively, with several prospective RCTs
being performed. When comparing bic in monotherapy
with castration, bic was associated with worse survival
rates, although the difference in median survival was only
6 weeks (Tyrrell et al. 1998). Two small RCTs, comparing
bic with complete androgen blockade, remained incon-
clusive, although Boccardo et al. showed an increased risk
of death in poorly differentiated tumors (Fourcade et al.
1998, Boccardo et al. 2002).
Despite these inconclusive results, the American
Society of Clinical Oncology (ASCO) has suggested bic
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
monotherapy as an alternative for the gold standard (ADT)
in well-informed patients with favorable clinical para-
meters (Loblaw et al. 2007).
NilutamideThere are nocomparative trials ofnil monotherapy
with castration or with other antiandrogens, because of
which nil is currently not licensed for monotherapy.
Enzalutamide In patients who progressed during docetaxel
therapy, enz has been shown to increase overall survival
in comparison with placebo in mCRPC patients in the
AFFIRM trial, leading to its FDA approval (Scher et al. 2012,
Ning et al. 2013). A recent report from the AFFIRM trial
showed comparable efficacy, safety, and tolerability in
patients aged O75 years as well, suggesting its possible
future widespread use (Sternberg et al. 2014). Two small
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T112
retrospective studies demonstrated only a limited activity
of enz in the post-docetaxel and post-abiraterone patient
population, suggesting the existence of cross-resistance
(Bianchini et al. 2013a, Schrader et al. 2013). These studies
are not RCTs and lack power with only 35–39 patients
being investigated, limiting its clinical value. However,
the molecular basis of such cross-resistance should be
further investigated because it will provide information on
the sequence in which these treatments should be used.
To test its efficacy in the pre-chemotherapy setting,
the PREVAIL trial was started (NCT01212991). However,
it has recently been stopped early after meeting its
co-primary endpoints of overall survival and radiographic
progression-free survival, making it possible for patients
from the placebo group to switch treatment arms.
Mechanismof action of antiandrogens Antiandro-
gens bind to the ligand-binding pocket of the AR and
thereby prevent its activation. When androgens such as
dihydrotestosterone (DHT) bind to the AR, a very specific
conformational change occurs in the ligand-binding
domain, leading to an active receptor (Pereira de Jesus-Tran
et al. 2006; Fig. 4). Crystal structures of steroid receptor
ligand binding domains (LBDs) with an agonist have shown
that after binding, helix 12 closes off the pocket and forms a
platform for the binding of coactivators, called activation
function 1 (AF1; Shiau et al. 1998, Williams & Sigler 1998).
This specific position of helix 12 is required and can only be
induced by agonists. When antagonists bind, they induce
a distinct inactive LBD conformation in which helix 12 is
repositioned from its active position or helix 12 is forced
into a flexible position (Kauppi et al. 2003, Hodgson et al.
2008, Lusher et al. 2011). This disables the binding
of coactivators and/or enables the formation of another
platform to which corepressors can bind. Moreover,
antiandrogens can recruit corepressors via other domains
such as the amino terminal domain (NTD), which was
demonstrated for CPA (Dotzlaw et al. 2002). For the AR,
the carboxy-terminal end of helix 12 is anchored by the
formation of a b-sheet leading to a less flexible helix 12.
In absence of antagonist-bound AR crystals, molecular
modeling techniques have predicted that, for the AR, a
displacement of helix 12 could occur in the presence of
antiandrogens, although involvement of residues in helix 5
and helix 11 cannot be excluded (Georget et al. 2002, Bohl
et al. 2005a, Bisson et al. 2008, Osguthorpe & Hagler 2011).
The conformation of the receptor induced by antagonists
results in the inhibition of many required actions of the AR,
such as inhibition of entry to the cell nucleus, binding to
DNA response elements, recruitment of coactivators, etc.
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
Each step is important for the execution of the normal
function of AR, and each step is therefore a potential target
for antiandrogen therapy. The precise mechanism of action
of bic and enz is described below (Fig. 4).
Bicalutamide When bic binds to the ligand-binding pocket
of the AR, a displacement of helix 12 and consequently
a distortion of the coactivator platform were suggested
by molecular dynamics-based simulations (Osguthorpe &
Hagler 2011). Furthermore, it leads to the assembly of
a transcriptionally inactive complex due to the inability
of the bic-bound AR to recruit coactivators and/or the
preferential recruitment of corepressors, NCoR and SMRT
(Masiello et al. 2002). By fluorescence recovery after
photobleaching (FRAP) analysis with a GFP-tagged AR,
the immobile fraction of nuclear AR disappeared when bic
was present, meaning that the receptor was unable to bind
DNA (Farla et al. 2005). Moreover, the AR was shown to
be destabilized in the presence of bic (Waller et al. 2000).
All these observations explain why bic can decrease
androgen-induced gene expression and reduce the weight
of rat ventral prostate and seminal vesicles after oral
administration (Furr & Tucker 1996).
Enzalutamide As mentioned earlier, enz is considered as a
more effective inhibitor of AR compared with bic due to
a higher binding affinity, the inhibition of AR nuclear
translocation and DNA binding by AR (Tran et al. 2009,
Guerrero et al. 2013). FoxA1 is a PCa-involved pioneering
factor that makes DNA more accessible for binding by the
AR. Enz prevented the AR from binding to DNA response
elements in presence of FoxA1, while bic could not (Belikov
et al. 2012). Further optimization of enz is ongoing and has
led to the development of ARN-509, a compound with
optimized pharmacokinetics, phase 1 and 2 clinical studies
of which are currently running (Clegg et al. 2012, Rathkopf
et al. 2013). Due to its structural similarities (Fig. 5), a
similar binding mode to AR and thus a similar working
mechanism are attributed to ARN-509 (Clegg et al. 2012,
Balbas et al. 2013). Unfortunately, so far no antagonist-
containing WT AR LBD crystal structures are available
(Balbas et al. 2013, Joseph et al. 2013, Korpal et al. 2013).
The discovery of the AR W741C/L mutation in bic-resistant
cells, AR T877A mutation in flut-resistant cells, and AR
F876L mutation in enz-resistant cells has given some
insights. A model for the binding of enz to the ligand-
binding pocket of WT AR has been proposed (Fig. 6; Balbas
et al. 2013). A focused chemical screen, based on this in silico
model, has led to a compound that circumvents this escape
mutation and remains antagonistic (Balbas et al. 2013).
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
A
B
R752
R752
Figure 6
Similar binding modes of bic and enz to the AR ligand-binding pocket.
In silicomodel of bic (A) and enz (B) binding as an antagonist in the ligand-
binding domain of the human AR according to Voet et al. (2013). Both
molecules show key conserved interactions in the deeper end of the pocket
where the common trifluoromethyl cyano benzyl group is accommodated
in a highly hydrophobic area with the exception of one hydrogen bridge
with arginine 752 (R752).
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T113
This was confirmed not only by transfection experiments
with AR F876L (where ARN-509 also performed as an
agonist), but also by the detection of the AR F876L
mutation in the plasma DNA of ARN-509-treated CRPC
patients (Balbas et al. 2013, Joseph et al. 2013).
Structural similarities for the current anti-
androgens Strikingly, the available first- and second-
generation antiandrogens share a common structural
element, an anilide core motif (Fig. 6). For some
compounds, the amide of the anilide can be a part of
(thio)hydantoin. The benzene ring of the anilide has a
trifluoromethyl group in meta-position and a nitro- or
cyano-group in para-position. The chemical scaffold of
Bic has been studied well by means of structure–activity
relationships (Kirkovsky et al. 2000, Bohl et al. 2005b) and
has also served as a template for the development of
several selective AR modulators (SARMs), such as Ostarine
and LGD-4033 (Dalton et al. 2013). The structures of
RD162, MDV3100 (enz), and ARN-509 are based on that
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
of RU59063, a non-steroidal arylthiohydantoin AR agonist
that binds AR with the highest known affinity (in the
nanomolar range) (Jung et al. 2010). Holding on to this
structural element, however, diminishes the structural
diversity of AR ligands and could therefore be the cause of
cross-resistance in case of sequential therapy. Molecular
modeling of bic and enz in the ligand-binding pocket
of AR shows a highly conserved interaction required for
binding to AR (Voet et al. 2013; Fig. 6). Structurally more
diverse AR LBD antagonists could thus provide an
innovative way of inhibiting AR, by introducing a
different conformational change in AR and hence also a
different helix 12 position.
From the latest studies on enz resistance and the much
earlier reports of bic and flut resistance, it is almost certain
that eventually every LBD inhibitor, which has been and
will be developed, will lead to the introduction of a
somatic mutation that causes a switch to agonist. There-
fore, it seems that the future of AR antagonists lies in the
development of compounds with different targets or
different strategies. For instance, compounds that do not
act via the ligand-binding pocket but via other sites on the
LBD, the NTD or compounds that could affect AR protein
levels will be of interest. Furthermore, the combination
of compounds with a complementary action mechanism
could lead to a more efficient inhibitory action of AR and
thus a better control of the disease.
Experimental AR-targeted therapiesInhibitors binding to the ligand-binding pocket We and others
have screened for novel AR antagonists belonging to
classes that are structurally different from those that are
currently used in the clinic (Helsen et al. 2012b, Voet et al.
2013). Although such molecules have the advantage that
they might still work in case of resistance to bic, flut, or
enz, they still need to be developed further before they
could be tested in a clinical trial setting.
ODM-201 is a novel AR antagonist that binds to AR
with a higher affinity than enz. Antiproliferative effects
of ODM-201 have been demonstrated in subcutaneous
VCaP xenografts and, due to its unique pharmacological
properties, it has also been shown to have superior
preclinical efficacy in phase 1 studies with no side effects
on the CNS. The most common adverse effects were
asthenia, diarrhea, and nausea (Fizazi et al. 2012).
Inhibitors of AR that do not bind to the ligand-binding pocketEPI-001 is
a bisphenol A diglycidyl ether-like compound that has
been reported to affect the transactivation mediated by the
AR NTD. It inhibits the AR regardless of ligand and inhibits
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T114
androgen-induced gene expression and proliferation both
in vitro and in LNCaP xenograft mice models (Andersen
et al. 2010, Myung et al. 2013). EPI-001 is an alternative
drug candidate for PCa as it does not act via the LBD.
EPI-001 might circumvent escape mechanisms such as
LBD mutation or truncation and should therefore still be
active in many forms of CRPC.
An alternative way of action compared with enz and bic
was discovered for ASC-J9, an AR-binding compound that
destabilizes full-length AR as well as the AR splice variants
involved in castration resistance of PCa (Yamashita et al.
2012). They all inhibit PCa proliferation and reduce PSA
levels, but only ASC-J9 was able to suppress cell invasion
and thus the formation of metastases in in vitro and in vivo
models (Lin et al. 2013a). A different modulation of the
STAT3–CCL2 signaling pathway was suggested to lie at the
base of this observed difference (Lin et al. 2013b).
Affecting AR localization SNARE-1 binds WT and mutant ARs
via the LBD. It not only inhibits nuclear translocation of
the AR, but also facilitates nuclear export leading to
reduced nuclear AR levels. Furthermore, it promotes
degradation of the AR via the ubiquitination pathway.
Its mechanism of action is completely different compared
with the clinically available antiandrogens and its activity
has been demonstrated on PCa xenografts in mice
(Narayanan et al. 2010).
Affecting AR mRNA half-life EZN-4176 is a 16-mer antisense
oligonucleotide that decreases full-length AR protein
expression by binding to exon 4 of AR mRNA (the
hinge). Both in vitro and in animal models, EZN-4176
can inhibit the proliferation of androgen-sensitive and
CRPC cells (Zhang et al. 2011). A small study with 22 CRPC
patients who were progressive (prior abiraterone or
enzalutamide treatment was allowed) demonstrated only
little biochemical and soft tissue response and only three
out of eight patients showed a reduction in circulating
tumor cells at the doses used (Bianchini et al. 2013b); side
effects such as fatigue and liver toxicity prevented further
dose escalation (Bianchini et al. 2013b).
Inhibitors binding to BF3 of AR Next to the ligand-binding
pocket, a newly discovered surface pocket of AR, called
binding function 3 (BF3), could be targeted to influence
coactivator binding (Estebanez-Perpina et al. 2007). Several
structural scaffolds have been identified through virtual
screening as binders to this BF3 region and were confirmed
to have antagonistic effects not only on AR transcriptional
activity (Lack et al. 2011), but also on proliferation of
LNCaP and enz-resistant cells (Munuganti et al. 2013).
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
Future perspectives
A new era has started in treating mCRPC patients thanks
to the development of multiple new potent AR-targeted
therapies. These agents first have to prove their efficacy in
the post-chemotherapeutic setting, as have abiraterone and
enzalutamide, leading to their FDA and EMA approval. For
ARN-509, a safety, pharmacokinetic, and proof-of-concept
study is currently ongoing (NCT01171898). The efficacy of
these AR-targeted compounds in these advanced stages has
confirmed that CRPC is not an AR-independent disease
and these novel treatments are even being considered to be
used at an earlier stage during the course of the disease.
When resistance to these novel agents will arise, the eluci-
dation of the underlying mechanisms will tell us what
the targets of the next generation of compounds should be.
The emergence of AR splice variants and the antagonist-
to-agonist switching mutation AR F876L indicate that the
AR can also circumvent the new LBD inhibitors, which
are being developed and might necessitate the develop-
ment of structurally or strategically different AR inhibitors.
Will the AR keep its critical role in PCa treatment or will
it be replaced by completely different targets?
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the review.
Funding
This work was supported by the fund from the KU Leuven (OT08-11) and
the FWO (G.0684-12/N and G.0830-13N), and the authors gratefully
acknowledge the financial support from the company Ravago Distribution
Center NV (LUOR fonds).
Acknowledgements
The authors would like to acknowledge Servier for producing Figs 2 and 4
using Servier Medical Art (www.servier.com).
References
Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T,
Yang YC, Banuelos CA et al. 2010 Regression of castrate-recurrent
prostate cancer by a small-molecule inhibitor of the amino-terminus
domain of the androgen receptor. Cancer Cell 17 535–546. (doi:10.1016/
j.ccr.2010.04.027)
Armstrong AJ, Haggman M, Stadler WM, Gingrich JR, Assikis V, Polikoff J,
Damber JE, Belkoff L, Nordle O, Forsberg G et al. 2013 Long-term
survival and biomarker correlates of tasquinimod efficacy in a multi-
center randomized study of men with minimally symptomatic
metastatic castration-resistant prostate cancer. Clinical Cancer Research
19 6891–6901. (doi:10.1158/1078-0432.CCR-13-1581)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T115
Attard G, Reid AH, A’Hern R, Parker C, Oommen NB, Folkerd E, Messiou C,
Molife LR, Maier G, Thompson E et al. 2009 Selective inhibition of
CYP17 with abiraterone acetate is highly active in the treatment of
castration-resistant prostate cancer. Journal of Clinical Oncology 27
3742–3748. (doi:10.1200/JCO.2008.20.0642)
Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA,
Chen Y, Greene GL, Shen Y & Sawyers CL 2013 Overcoming mutation-
based resistance to antiandrogens with rational drug design. eLife 2
e00499. (doi:10.7554/eLife.00499)
Belikov S, Oberg C, Jaaskelainen T, Rahkama V, Palvimo JJ & Wrange O
2012 FoxA1 corrupts the antiandrogenic effect of bicalutamide but only
weakly attenuates the effect of MDV3100 (Enzalutamide). Molecular and
Cellular Endocrinology 365 95–107. (doi:10.1016/j.mce.2012.10.002)
Bianchini D, Lorente D, Rodriguez-Vida A, Omlin A, Pezaro C, Ferraldeschi R,
Zivi A, Attard G, Chowdhury S & de Bono JS 2013aAntitumour activity of
enzalutamide (MDV3100) in patients with metastatic castration-resistant
prostate cancer (CRPC) pre-treated with docetaxel and abiraterone.
European Journal of Cancer 50 78–84. (doi:10.1016/j.ejca.2013.08.020)
Bianchini D, Omlin A, Pezaro C, Lorente D, Ferraldeschi R, Mukherji D,
Crespo M, Figueiredo I, Miranda S, Riisnaes R et al. 2013b First-
in-human Phase I study of EZN-4176, a locked nucleic acid antisense
oligonucleotide to exon 4 of the androgen receptor mRNA in patients
with castration-resistant prostate cancer. British Journal of Cancer 109
2579–2586. (doi:10.1038/bjc.2013.619)
Bisson WH, Abagyan R & Cavasotto CN 2008 Molecular basis of agonicity
and antagonicity in the androgen receptor studied by molecular
dynamics simulations. Journal of Molecular Graphics & Modelling 27
452–458. (doi:10.1016/j.jmgm.2008.08.001)
Boccardo F, Barichello M, Battaglia M, Carmignani G, Comeri G, Ferraris V,
Lilliu S, Montefiore F, Portoghese F, Cortellini P et al. 2002 Bicalutamide
monotherapy versus flutamide plus goserelin in prostate cancer:
updated results of a multicentric trial. European Urology 42 481–490.
(doi:10.1016/S0302-2838(02)00435-9)
Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P,
Hubert J, Soret JY, Mangin P, Mallo C et al. 1997 Flutamide versus
orchidectomy in the treatment of metastatic prostate carcinoma.
European Urology 32 391–395 discussion 395–396.
Bohl CE, Gao W, Miller DD, Bell CE & Dalton JT 2005a Structural basis for
antagonism and resistance of bicalutamide in prostate cancer. PNAS
102 6201–6206. (doi:10.1073/pnas.0500381102)
Bohl CE, Miller DD, Chen J, Bell CE & Dalton JT 2005b Structural basis for
accommodation of nonsteroidal ligands in the androgen receptor.
Journal of Biological Chemistry 280 37747–37754. (doi:10.1074/jbc.
M507464200)
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G,
Bodrogi I, Mackenzie MJ, Shen L et al. 2010 Prednisone plus cabazitaxel
or mitoxantrone for metastatic castration-resistant prostate cancer
progressing after docetaxel treatment: a randomised open-label trial.
Lancet 376 1147–1154. (doi:10.1016/S0140-6736(10)61389-X)
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN,
Jones RJ, Goodman OB Jr, Saad F et al. 2011 Abiraterone and increased
survival in metastatic prostate cancer. New England Journal of Medicine
364 1995–2005. (doi:10.1056/NEJMoa1014618)
Brawer MK 2001 The evolution of hormonal therapy for prostatic
carcinoma. Reviews in Urology 3 (Suppl 3) S1–S9.
Bruno RD, Vasaitis TS, Gediya LK, Purushottamachar P, Godbole AM,
Ates-Alagoz Z, Brodie AM & Njar VC 2011 Synthesis and biological
evaluations of putative metabolically stable analogs of VN/124-1
(TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1
(TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft
model. Steroids 76 1268–1279. (doi:10.1016/j.steroids.2011.06.002)
Bubley GJ 2001 Is the flare phenomenon clinically significant? Urology 58
5–9. (doi:10.1016/S0090-4295(01)01235-3)
Clegg NJ, Wongvipat J, Tran C, Ouk S, Dilhas A, Joseph J, Chen Y, Grillot K,
Bischoff ED, Cai L et al. 2012 ARN-509: a novel anti-androgen for
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
prostate cancer treatment. Cancer Research 72 1494–1503. (doi:10.1158/
0008-5472.CAN-11-3948)
Crawford ED, Tombal B, Miller K, Boccon-Gibod L, Schroder F, Shore N,
Moul JW, Jensen JK, Olesen TK & Persson BE 2011 A phase III extension
trial with a 1-arm crossover from leuprolide to degarelix: comparison of
gonadotropin-releasing hormone agonist and antagonist effect on
prostate cancer. Journal of Urology 186 889–897. (doi:10.1016/j.juro.
2011.04.083)
Dalton JT, Taylor RP, Mohler ML & Steiner MS 2013 Selective androgen
receptor modulators for the prevention and treatment of muscle
wasting associated with cancer. Current Opinion in Supportive and
Palliative Care 7 345–351. (doi:10.1097/SPC.0000000000000015)
Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR,
Taplin ME, Bubley GJ, Kheoh T, Haqq C et al. 2010 Phase II multicenter
study of abiraterone acetate plus prednisone therapy in patients with
docetaxel-treated castration-resistant prostate cancer. Journal of Clinical
Oncology 28 1496–1501. (doi:10.1200/JCO.2009.25.9259)
Dawson NA,Conaway M, Halabi S,Winer EP, Small EJ, LakeD & VogelzangNJ
2000 A randomized study comparing standard versus moderately
high dose megestrol acetate for patients with advanced prostate
carcinoma: cancer and leukemia group B study 9181. Cancer 88 825–834.
(doi:10.1002/(SICI)1097-0142(20000215)88:4!825::AID-CNCR13O3.0.
CO;2-N)
Denayer S, Helsen C, Thorrez L, Haelens A & Claessens F 2010 The rules of
DNA recognition by the androgen receptor. Molecular Endocrinology 24
898–913. (doi:10.1210/me.2009-0310)
Dotzlaw H, Moehren U, Mink S, Cato AC, Iniguez Lluhi JA & Baniahmad A
2002 The amino terminus of the human AR is target for corepressor
action and antihormone agonism. Molecular Endocrinology 16 661–673.
(doi:10.1210/mend.16.4.0798)
Estebanez-Perpina E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R,
Pallai P, Shokat KM, Baxter JD, Guy RK et al. 2007 A surface on the
androgen receptor that allosterically regulates coactivator binding.
PNAS 104 16074–16079. (doi:10.1073/pnas.0708036104)
Farla P, Hersmus R, Trapman J & Houtsmuller AB 2005 Antiandrogens
prevent stable DNA-binding of the androgen receptor. Journal of Cell
Science 118 4187–4198. (doi:10.1242/jcs.02546)
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW,
Comber H, Forman D & Bray F 2013 Cancer incidence and mortality
patterns in Europe: estimates for 40 countries in 2012. European
Journal of Cancer 49 1374–1403. (doi:10.1016/j.ejca.2012.12.027)
Fizazi K, Massard C, James N, Culine S, Jones R, Oksala R, Moilanen A,
Aho E, Ravanti L & Kallio P 2012 ARADES trial: a first-in-man,
open-label, phase I/II safety, pharmacokinetic, and proof-of-concept
study of ODM-201 in patients with progressive metastatic castration-
resistant prostate cancer. In 2013 Genitourinary Cancers Symposium.
Journal of Clinical Oncology 31 (February 20 Supplement) abstract 65.
Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC,
Powlin SS, Dinchuk JE, Balog A et al. 2011 Drug safety is a barrier to the
discovery and development of new androgen receptor antagonists.
Prostate 71 480–488. (doi:10.1002/pros.21263)
Fourcade RO, Chatelain C & Poterre M 1998 An open multicentre
randomised study to compare the effect and safety of ‘Casodex’
(bicalutamide) 150 mg monotherapy with castration plus nilutamide in
metastatic prostate cancer In 13th EAU Congress, p88 (abstract #349).
Barcelona, Spain: European Urology.
Furr BJ 1996 The development of Casodex (bicalutamide): preclinical
studies. European Urology 29 (Suppl 2) 83–95.
Furr BJ & Tucker H 1996 The preclinical development of bicalutamide:
pharmacodynamics and mechanism of action. Urology 47 13–25
discussion 29–32. (doi:10.1016/S0090-4295(96)80003-3)
Garnick MB & Mottet N 2012 New treatment paradigm for prostate
cancer: abarelix initiation therapy for immediate testosterone
suppression followed by a luteinizing hormone-releasing hormone
agonist. BJU International 110 499–504. (doi:10.1111/j.1464-410X.
2011.10708.x)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T116
Georget V, Terouanne B, Nicolas JC & Sultan C 2002 Mechanism of
antiandrogen action: key role of hsp90 in conformational change and
transcriptional activity of the androgen receptor. Biochemistry 41
11824–11831. (doi:10.1021/bi0259150)
Guerrero J, Alfaro IE, Gomez F, Protter AA & Bernales S 2013 Enzalutamide,
an androgen receptor signaling inhibitor, induces tumor regression in a
mouse model of castration-resistant prostate cancer. Prostate 73
1291–1305. (doi:10.1002/pros.22674)
Harrison MR, Wong TZ, Armstrong AJ & George DJ 2013 Radium-223
chloride: a potential new treatment for castration-resistant prostate
cancer patients with metastatic bone disease. Cancer Management and
Research 5 1–14. (doi:10.2147/CMAR.S25537)
Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V,
Mottet N, Schmid HP, van der Kwast T, Wiegel T et al. 2011 EAU
guidelines on prostate cancer. Part 1: screening, diagnosis, and
treatment of clinically localised disease. European Urology 59 61–71.
(doi:10.1016/j.eururo.2010.10.039)
Helsen C, Kerkhofs S, Clinckemalie L, Spans L, Laurent M, Boonen S,
Vanderschueren D & Claessens F 2012a Structural basis for nuclear
hormone receptor DNA binding. Molecular and Cellular Endocrinology
348 411–417. (doi:10.1016/j.mce.2011.07.025)
Helsen C, Marchand A, Chaltin P, Munck S, Voet A, Verstuyf A & Claessens F
2012b Identification and characterization of MEL-3, a novel AR
antagonist that suppresses prostate cancer cell growth. Molecular Cancer
Therapeutics 11 1257–1268. (doi:10.1158/1535-7163.MCT-11-0763)
Hendriksen PJ, Dits NF, Kokame K, Veldhoven A, van Weerden WM,
Bangma CH, Trapman J & Jenster G 2006 Evolution of the androgen
receptor pathway during progression of prostate cancer. Cancer Research
66 5012–5020. (doi:10.1158/0008-5472.CAN-05-3082)
Higano CS & Crawford ED 2011 New and emerging agents for the
treatment of castration-resistant prostate cancer. Urologic Oncology 29
S1–S8. (doi:10.1016/j.urolonc.2011.08.013)
Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L,
Provost N & Frohlich MW 2009 Integrated data from 2 randomized,
double-blind, placebo-controlled, phase 3 trials of active cellular
immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer
115 3670–3679. (doi:10.1002/cncr.24429)
Hodgson MC, Shen HC, Hollenberg AN & Balk SP 2008 Structural basis for
nuclear receptor corepressor recruitment by antagonist-liganded
androgen receptor. Molecular Cancer Therapeutics 7 3187–3194.
(doi:10.1158/1535-7163.MCT-08-0461)
Huggins C 1942 Effect of orchiectomy and irradiation on cancer of the
prostate. Annals of Surgery 115 1192–1200. (doi:10.1097/00000658-
194206000-00030)
Irani J, Salomon L, Oba R, Bouchard P & Mottet N 2010 Efficacy of
venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for
the treatment of vasomotor hot flushes in men taking gonadotropin-
releasing hormone analogues for prostate cancer: a double-blind,
randomised trial. Lancet Oncology 11 147–154. (doi:10.1016/
S1470-2045(09)70338-9)
Jacobi GH, Altwein JE, Kurth KH, Basting R & Hohenfellner R 1980
Treatment of advanced prostatic cancer with parenteral cyproterone
acetate: a phase III randomised trial. British Journal of Urology 52
208–215. (doi:10.1111/j.1464-410X.1980.tb02961.x)
Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M,
Maneval EC, Chen I, Darimont B et al. 2013 A clinically relevant
androgen receptor mutation confers resistance to second-generation
antiandrogens enzalutamide and ARN-509. Cancer Discovery 3
1020–1029. (doi:10.1158/2159-8290.CD-13-0226)
Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C & Wongvipat J 2010
Structure–activity relationship for thiohydantoin androgen receptor
antagonists for castration-resistant prostate cancer (CRPC). Journal of
Medicinal Chemistry 53 2779–2796. (doi:10.1021/jm901488g)
Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, Calles K,
Engstrom O, Harlan J, Muchmore S et al. 2003 The three-dimensional
structures of antagonistic and agonistic forms of the glucocorticoid
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
receptor ligand-binding domain: RU-486 induces a transconformation
that leads to active antagonism. Journal of Biological Chemistry 278
22748–22754. (doi:10.1074/jbc.M212711200)
Kirkovsky L, Mukherjee A, Yin D, Dalton JT & Miller DD 2000 Chiral
nonsteroidal affinity ligands for the androgen receptor.1. Bicalutamide
analogues bearing electrophilic groups in the B aromatic ring. Journal of
Medicinal Chemistry 43 581–590. (doi:10.1021/jm990027x)
Knudsen KE & Kelly WK 2012 Outsmarting androgen receptor: creative
approaches for targeting aberrant androgen signaling in advanced
prostate cancer. Expert Review of Endocrinology & Metabolism 6 483–493.
(doi:10.1586/eem.11.33)
Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, Yuan J,
Kovats SG, Kim S, Cooke VG et al. 2013 An F876L mutation in
androgen receptor confers genetic and phenotypic resistance to
MDV3100 (enzalutamide). Cancer Discovery 3 1030–1043.
(doi:10.1158/2159-8290.CD-13-0142)
Lack NA, Axerio-Cilies P, Tavassoli P, Han FQ, Chan KH, Feau C, LeBlanc E,
Guns ET, Guy RK, Rennie PS et al. 2011 Targeting the binding function
3 (BF3) site of the human androgen receptor through virtual screening.
Journal of Medicinal Chemistry 54 8563–8573. (doi:10.1021/jm201098n)
Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL,
Milani RV, Sagalowsky AI, Smith MR & Zakai N 2010 Androgen-
deprivation therapy in prostate cancer and cardiovascular risk:
a science advisory from the American Heart Association, American
Cancer Society, and American Urological Association: endorsed by
the American Society for Radiation Oncology. Circulation 121
833–840. (doi:10.1161/CIRCULATIONAHA.109.192695)
Lin TH, Lee SO, Niu Y, Xu D, Liang L, Li L, Yeh SD, Fujimoto N, Yeh S &
Chang C 2013a Differential androgen deprivation therapies with anti-
androgens casodex/bicalutamide or MDV3100/Enzalutamide versus
anti-androgen receptor ASC-J9(R) Lead to promotion versus suppres-
sion of prostate cancer metastasis. Journal of Biological Chemistry 288
19359–19369. (doi:10.1074/jbc.M113.477216)
Lin TH, Izumi K, Lee SO, Lin WJ, Yeh S & Chang C 2013b Anti-androgen
receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or
Casodex (Bicalutamide) leads to opposite effects on prostate cancer
metastasis via differential modulation of macrophage infiltration and
STAT3-CCL2 signaling. Cell Death & Disease 4 e764. (doi:10.1038/cddis.
2013.270)
Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS,
Middleton R, Sharp SA, Smith TJ, Talcott J et al. 2007 Initial hormonal
management of androgen-sensitive metastatic, recurrent, or pro-
gressive prostate cancer: 2006 update of an American Society of Clinical
Oncology practice guideline. Journal of Clinical Oncology 25 1596–1605.
(doi:10.1200/JCO.2006.10.1949)
Lusher SJ, Raaijmakers HC, Vu-Pham D, Dechering K, Lam TW, Brown AR,
Hamilton NM, Nimz O, Bosch R, McGuire R et al. 2011 Structural basis
for agonism and antagonism for a set of chemically related
progesterone receptor modulators. Journal of Biological Chemistry 286
35079–35086. (doi:10.1074/jbc.M111.273029)
Mahler C & Denis L 1990 Clinical profile of a new non-steroidal
antiandrogen. Journal of Steroid Biochemistry and Molecular Biology 37
921–924. (doi:10.1016/0960-0760(90)90444-P)
Marques RB, Dits NF, Erkens-Schulze S, van Ijcken WF, van Weerden WM &
Jenster G 2011 Modulation of androgen receptor signaling in hormonal
therapy-resistant prostate cancer cell lines. PLoS ONE 6 e23144.
(doi:10.1371/journal.pone.0023144)
Masiello D, Cheng S, Bubley GJ, Lu ML & Balk SP 2002 Bicalutamide
functions as an androgen receptor antagonist by assembly of a
transcriptionally inactive receptor. Journal of Biological Chemistry 277
26321–26326. (doi:10.1074/jbc.M203310200)
Massard C & Fizazi K 2011 Targeting continued androgen receptor
signaling in prostate cancer. Clinical Cancer Research 17 3876–3883.
(doi:10.1158/1078-0432.CCR-10-2815)
McLeod DG 1997 Tolerability of nonsteroidal antiandrogens in the
treatment of advanced prostate cancer. Oncologist 2 18–27.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T117
Moffat LE 1990 Comparison of Zoladex, diethylstilbestrol and cyproterone
acetate treatment in advanced prostate cancer. European Urology
18 (Suppl 3) 26–27.
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS,
True LD & Nelson PS 2008 Maintenance of intratumoral androgens in
metastatic prostate cancer: a mechanism for castration-resistant
tumor growth. Cancer Research 68 4447–4454. (doi:10.1158/0008-5472.
CAN-08-0249)
Munuganti RS, Leblanc E, Axerio-Cilies P, Labriere C, Frewin K, Singh K,
Hassona MD, Lack NA, Li H, Ban F et al. 2013 Targeting the binding
function 3 (BF3) site of the androgen receptor through virtual
screening. 2. development of 2-((2-phenoxyethyl) thio)-1H-benzimi-
dazole derivatives. Journal of Medicinal Chemistry 56 1136–1148.
(doi:10.1021/jm3015712)
Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, Yang YC,
Tavakoli I, Haile S, Watt K et al. 2013 An androgen receptor N-terminal
domain antagonist for treating prostate cancer. Journal of Clinical
Investigation 123 2948–2960. (doi:10.1172/JCI66398)
NarayananR,YepuruM,Szafran AT,SzwarcM,BohlCE,YoungNL,MillerDD,
Mancini MA & Dalton JT 2010 Discovery and mechanistic characteri-
zation of a novel selective nuclear androgen receptor exporter for the
treatment of prostate cancer. Cancer Research 70 842–851. (doi:10.1158/
0008-5472.CAN-09-3206)
Ning YM, Pierce W, Maher VE, Karuri S, Tang S, Chiu HJ, Palmby T,
Fourie Zirkelbach J, Marathe D, Mehrotra N et al. 2013 Enzalutamide
for treatment of patients with metastatic castration-resistant prostate
cancer who have previously received docetaxel: U.S. Food and Drug
Administration Drug Approval Summary. Clinical Cancer Research 19
6067–6073. (doi:10.1158/1078-0432.CCR-13-1763)
Osguthorpe DJ & Hagler AT 2011 Mechanism of androgen receptor
antagonism by bicalutamide in the treatment of prostate cancer.
Biochemistry 50 4105–4113. (doi:10.1021/bi102059z)
Ozono S, Ueda T, Hoshi S, Yamaguchi A, Maeda H, Fukuyama Y, Takeda K,
Ohashi Y, Tsukamoto T, Naito S et al. 2012 The efficacy and safety of
degarelix, a GnRH antagonist: a 12-month, multicentre, randomized,
maintenance dose-finding phase II study in Japanese patients with
prostate cancer. Japanese Journal of Clinical Oncology 42 477–484.
(doi:10.1093/jjco/hys035)
Patel SR, Kvols LK, Hahn RG, Windschitl H, Levitt R & Therneau T 1990
A phase II randomized trial of megestrol acetate or dexamethasone in
the treatment of hormonally refractory advanced carcinoma of the
prostate. Cancer 66 655–658. (doi:10.1002/1097-
0142(19900815)66:4!655::AID-CNCR2820660409O3.0.CO;2-P)
Pavone-Macaluso M, de Voogt HJ, Viggiano G, Barasolo E, Lardennois B,
de Pauw M & Sylvester R 1986 Comparison of diethylstilbestrol,
cyproterone acetate and medroxyprogesterone acetate in the treatment
of advanced prostatic cancer: final analysis of a randomized phase III
trial of the European Organization for Research on Treatment of Cancer
Urological Group. Journal of Urology 136 624–631.
Pavone-Macaluso M, Schroder FH, de Voogt HJ, Viggiano G, Barasolo E,
Lardennois B, de Pauw M, Sylvester R, Smith PH & Suciu S 1989 EORTC
protocol 30761: a randomized study of non-metastatic and metastatic
prostatic cancer treated by cyproterone acetate versus diethylstilbestrol
and medroxyprogesterone acetate, European Organization for Research
on Treatment of Cancer Urological Group. Progress in Clinical and
Biological Research 303 111–116.
Pereira de Jesus-Tran K, Cote PL, Cantin L, Blanchet J, Labrie F & Breton R
2006 Comparison of crystal structures of human androgen receptor
ligand-binding domain complexed with various agonists reveals
molecular determinants responsible for binding affinity. Protein Science
15 987–999. (doi:10.1110/ps.051905906)
Pridjian G, Schmit V & Schreiber J 1987 Medroxyprogesterone acetate:
receptor binding and correlated effects on steroidogenesis in rat
granulosa cells. Journal of Steroid Biochemistry 26 313–319. (doi:10.1016/
0022-4731(87)90095-1)
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ,
Chow Maneval E, Chen I, Gonen M et al. 2013 Phase I study of
ARN-509, a novel antiandrogen, in the treatment of castration-resistant
prostate cancer. Journal of Clinical Oncology 31 3525–3530.
(doi:10.1200/JCO.2013.50.1684)
Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K,
Pezaro C, Carreira S, Goodall J, Arlt W et al. 2012 Interactions of
abiraterone, eplerenone, and prednisolone with wild-type and mutant
androgen receptor: a rationale for increasing abiraterone exposure
or combining with MDV3100. Cancer Research 72 2176–2182.
(doi:10.1158/0008-5472.CAN-11-3980)
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K,
Mainwaring P, Piulats JM, Ng S et al. 2013 Abiraterone in metastatic
prostate cancer without previous chemotherapy. New England
Journal of Medicine 368 138–148. (doi:10.1056/NEJMoa1209096)
Sarosdy MF 1999 Which is the optimal antiandrogen for use in combined
androgen blockade of advanced prostate cancer? The transition from a
first- to second-generation antiandrogen Anticancer Drugs 10 791–796.
(doi:10.1097/00001813-199910000-00001)
Sarosdy MF, Schellhammer PF, Soloway MS, Vogelzang NJ, Crawford ED,
Presti J, Chodak GW, Mitchell P & Porter L 1999 Endocrine effects, efficacy
and tolerability of a 10.8-mg depot formulation of goserelin acetate
administered every 13 weeks to patients with advanced prostate cancer.
BJU International 83 801–806. (doi:10.1046/j.1464-410x.1999.00028.x)
Schally AV, Comaru-Schally AM & Gonzalez-Barcena D 1992 Present status
of agonistic and antagonistic analogs of LH-RH in the treatment of
advanced prostate cancer. Biomedicine and Pharmacotherapy 46
465–471. (doi:10.1016/0753-3322(92)90004-Q)
Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL,
Sarosdy M, Vogelzang N, Jones J & Kolvenbag G 1996 Maximal
androgen blockade for patients with metastatic prostate cancer:
outcome of a controlled trial of bicalutamide versus flutamide, each in
combination with luteinizing hormone-releasing hormone analogue
therapy. Casodex Combination Study Group. Urology 47 54–60
discussion 80–84. (doi:10.1016/S0090-4295(96)80010-0)
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R,
Mulders P, Chi KN, Shore ND et al. 2012 Increased survival with
enzalutamide in prostate cancer after chemotherapy. New England
Journal of Medicine 367 1187–1197. (doi:10.1056/NEJMoa1207506)
Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T,
Jentzmik F, Stoeckle M, Schrader M, Herrmann E et al. 2013 Enzalutamide
in castration-resistant prostate cancer patients progressing after docetaxel
and abiraterone. European Urology 65 30–36. (doi:10.1016/j.eururo.2013.
06.042)
Schroder FH 1993 Cyproterone acetate – mechanism of action and clinical
effectiveness in prostate cancer treatment. Cancer 72 3810–3815.
(doi:10.1002/1097-0142(19931215)72:12C!3810::AID-
CNCR2820721710O3.0.CO;2-O)
Schroder FH, Whelan P, de Reijke TM, Kurth KH, Pavone-Macaluso M,
Mattelaer J, van Velthoven RF, Debois M & Collette L 2004 Metastatic
prostate cancer treated by flutamide versus cyproterone acetate. Final
analysis of the "European Organization for Research and Treatment
of Cancer" (EORTC) Protocol 30892. European Urology 45 457–464.
(doi:10.1016/j.eururo.2003.11.016)
Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen PC,
Bennett CL & Wilt TJ 2000 Single-therapy androgen suppression
in men with advanced prostate cancer: a systematic review and
meta-analysis. Annals of Internal Medicine 132 566–577. (doi:10.7326/
0003-4819-132-7-200004040-00009)
Sharifi R & Browneller R 2002 Serum testosterone suppression and
potential for agonistic stimulation during chronic treatment with
monthly and 3-month depot formulations of leuprolide acetate
for advanced prostate cancer. Journal of Urology 168 1001–1004.
(doi:10.1016/S0022-5347(05)64560-0)
Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA & Greene GL
1998 The structural basis of estrogen receptor/coactivator recognition
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Endocrine-RelatedCancer
Thematic Review C Helsen et al. Role of AR antagonists intreatment of PCa
21 :4 T118
and the antagonism of this interaction by tamoxifen. Cell 95 927–937.
(doi:10.1016/S0092-8674(00)81717-1)
Siegel R, Naishadham D & Jemal A 2013 Cancer statistics, 2013. CA: A
Cancer Journal for Clinicians 63 11–30. (doi:10.3322/caac.21166)
Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF,
Smith JA Jr, Scott M, Kennealey G & Gau TC 1991 Zoladex versus
orchiectomy in treatment of advanced prostate cancer: a randomized
trial. Zoladex Prostate Study Group. Urology 37 46–51. (doi:10.1016/
0090-4295(91)80077-K)
Sternberg CN, de Bono JS, Chi KN, Fizazi K, Mulders P, Cerbone L, Hirmand M,
Forer D & Scher HI 2014 Improved outcomes in elderly patients with
metastatic castration-resistant prostate cancer treated with the androgen
receptor inhibitor enzalutamide: results from the phase III AFFIRM trial.
Annals of Oncology 25 429–434. (doi:10.1093/annonc/mdt571)
Taplin ME & Balk SP 2004 Androgen receptor: a key molecule in the
progression of prostate cancer to hormone independence. Journal of
Cellular Biochemistry 91 483–490. (doi:10.1002/jcb.10653)
Thompson IM 2001 Flare associated with LHRH-agonist therapy. Reviews
in Urology 3 (Suppl 3) S10–S14.
Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC & O’Boyle PJ 1996 A
prospective, randomised study to compare goserelin acetate (Zoladex)
versus cyproterone acetate (Cyprostat) versus a combination of the
two in the treatment of metastatic prostatic carcinoma. European
Urology 29 47–54.
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J,
Smith-Jones PM, Yoo D, Kwon A et al. 2009 Development of a
second-generation antiandrogen for treatment of advanced prostate
cancer. Science 324 787–790. (doi:10.1126/science.1168175)
Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T,
Chamberlain M, Webster A & Blackledge G 1998 A randomised
comparison of ’Casodex’ (bicalutamide) 150 mg monotherapy versus
castration in the treatment of metastatic and locally advanced prostate
cancer. European Urology 33 447–456. (doi:10.1159/000019634)
Van PoppelH,TombalB,de laRosette JJ, PerssonBE, JensenJK & Kold Olesen T
2008 Degarelix: a novel gonadotropin-releasing hormone (GnRH)
receptor blocker – results from a 1-yr, multicentre, randomised, phase 2
dosage-finding study in the treatment of prostate cancer. European Urology
54 805–813. (doi:10.1016/j.eururo.2008.04.065)
Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK,
Guo Z, Fang HB, Njar VC & Brodie AM 2008 Androgen receptor
inactivation contributes to antitumor efficacy of 17a-hydroxyl-
ase/17,20-lyase inhibitor 3b-hydroxy-17-(1H-benzimidazole-1-yl)
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-13-0545 Printed in Great Britain
androsta-5,16-diene in prostate cancer. Molecular Cancer Therapeutics 7
2348–2357. (doi:10.1158/1535-7163.MCT-08-0230)
Voet A, Helsen C, Zhang KY & Claessens F 2013 The discovery of novel
human androgen receptor antagonist chemotypes using a combined
pharmacophore screening procedure. ChemMedChem 8 644–651.
(doi:10.1002/cmdc.201200549)
Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF,
Smith JA Jr, Caplan RJ & Kennealey GT 1995 Goserelin versus
orchiectomy in the treatment of advanced prostate cancer: final results
of a randomized trial. Zoladex Prostate Study Group. Urology 46
220–226. (doi:10.1016/S0090-4295(99)80197-6)
Waller AS, Sharrard RM, Berthon P & Maitland NJ 2000 Androgen receptor
localisation and turnover in human prostate epithelium treated with
the antiandrogen, casodex. Journal of Molecular Endocrinology 24
339–351. (doi:10.1677/jme.0.0240339)
Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim R, Wang H,
Lupien M et al. 2009 Androgen receptor regulates a distinct
transcription program in androgen-independent prostate cancer. Cell
138 245–256. (doi:10.1016/j.cell.2009.04.056)
Wex J, Sidhu M, Odeyemi I, Abou-Setta AM, Retsa P & Tombal B 2013
Leuprolide acetate 1-, 3- and 6-monthly depot formulations in
androgen deprivation therapy for prostate cancer in nine European
countries: evidence review and economic evaluation. ClinicoEconomics
and Outcomes Research 5 257–269. (doi:10.2147/CEOR.S44855)
Williams SP & Sigler PB 1998 Atomic structure of progesterone complexed
with its receptor. Nature 393 392–396. (doi:10.1038/30775)
Yamaoka M, Hara T, Hitaka T, Kaku T, Takeuchi T, Takahashi J, Asahi S,
Miki H, Tasaka A & Kusaka M 2012 Orteronel (TAK-700), a novel
non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in
human and monkey adrenal cells and serum steroid levels in
cynomolgus monkeys. Journal of Steroid Biochemistry and Molecular
Biology 129 115–128. (doi:10.1016/j.jsbmb.2012.01.001)
Yamashita S, Lai KP, Chuang KL, Xu D, Miyamoto H, Tochigi T, Pang ST,
Li L, Arai Y, Kung HJ et al. 2012 ASC-J9 suppresses castration-resistant
prostate cancer growth through degradation of full-length and splice
variant androgen receptors. Neoplasia 14 74–83.
Zhang Y, Castaneda S, Dumble M, Wang M, Mileski M, Qu Z, Kim S, Shi V,
Kraft P, Gao Y et al. 2011 Reduced expression of the androgen receptor
by third generation of antisense shows antitumor activity in models of
prostate cancer. Molecular Cancer Therapeutics 10 2309–2319.
(doi:10.1158/1535-7163.MCT-11-0329)
Received in final form 21 February 2014Accepted 13 March 2014Made available online as an Accepted Preprint17 March 2014
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 08/01/2021 08:15:59AMvia free access
Recommended