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R EVI E W A R T IC L E
Targeting the androgen receptor
signalling axis in castration-resistant
prostate cancer (CRPC)
BJUI
BJU INTERNATIONAL
Che-Kai Tsao, Matthew D. Galsky, Alexander C. Small,
Tiffany Yee and William K. Oh
Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai
School of Medicine, New York, NY, USA
Accepted for publication 31 May 2012
What’s known on the subject? and What does the study add?
Castration resistance has been appreciated for decades, and several mechanisms
theorising on this effect have been proposed. A rich pipeline of novel agents, including
abiraterone and MDV3100, have provided proof of principle that novel agents targeting
the AR signalling pathway with superior selectivity and activity than predecessors have
yielded significant clinical benefit for patients with metastatic castration-resistant
prostate cancer.
Our review provides an update in the development of several novel agents targeting the
AR signalling pathway now in clinical testing, as well as review novel therapies in
development with distinct mechanisms of action showing promising preclinical activity.
• Despite undergoing local therapy with curative intent, 20–30% of patients with prostate
cancer will ultimately development metastatic disease, leading to morbidity and mortality.
• Androgen-deprivation therapy (ADT) for men with metastatic prostate cancer results in
transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum
testosterone, a clinical state classically referred to as ‘hormone refractory’ disease.
• In this review, we examine mechanisms of resistance to ADT that have redefined our
understanding of the more appropriately termed ‘castration resistant’ disease, and have
paved the way for a new generation of therapeutics targeting the androgen signalling axis
in advanced prostate cancer.
KEYWORDS
INTRODUCTION
prostate cancer, castration resistance, androgen deprivation, novel endocrine therapy,
hormone refractory, androgen receptor
Prostate cancer is the most common non-skin cancer in men in the Western world [1]. While
widespread PSA screening has significantly increased prostate cancer detection, about
one-third of men treated with definitive local therapy will have disease recurrence, while
another subset will present with advanced disease at the time of initial diagnosis [2].
Prostate cancer growth and progression is stimulated by androgens, acting through the
androgen receptor (AR). Circulating androgen levels are predominately regulated through the
hypothalamic-pituitary-adrenal-gonadal axis and androgen-deprivation therapy (ADT) results
in temporary disease regression in most patients. However, this approach eventually fails, as
tumours develop mechanisms to grow despite chemical or surgical castration and inevitably
leading to significant morbidity and mortality.
THE NORMAL PROSTATE AND THE AR
‘Prostate cancer growth and progression is
stimulated by androgens, acting through the
androgen receptor’
1580
The prostate is responsible for producing
most of the fluid in the seminal plasma
volume of men’s ejaculate. Binding of
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2 0 1 2 B J U I N T E R N A T I O N A L | 11 0 , 1 5 8 0 – 1 5 8 8 | doi:10.1111/j.1464-410X.2012.11445.x
TARGETING THE AR SIGNALLING AXIS IN CRPC
FIG. 1.
AR signalling and mechanisms
of castration resistance.
Testes
MECHANISMS OF CASTRATION RESISTANCE
Steroidogenesis
Ligand Dependent Ligand Independent
Adrenal gland
Persistent
intratumoral
androgens
DHT
AR
AR Splice
Variants
Autocrine
Androgen
Production
AR
AR
AR
AR
AR
Gene
Amplification
Tumour cell
proliferation
PROSTATE TUMOUR CELL
AR Mutation
Co-activators
Co-repressors
AR
Proteins
CYTOPLASM
NUCLEUS
RNA
AR
Epigenetic
changes
androgens to the AR, expressed in epithelial
and stromal cells of the prostate [3], results
in differentiation, metabolism, proliferation,
and survival of these cells. The AR is
composed of ligand-dependent intracellular
transcription factors that are known to
influence the development and growth of
prostate cancer. Mouse models show that
androgens are required at every step of
prostate development [4], as a nonfunctional AR results in a testicular
feminisation-like syndrome with absence of
the prostate [5]. While androgens are
produced by both the Leydig cells of the
testes (testosterone: 90–95%) and adrenal
gland (5-dehydroepiandrosterone [DHEA]
and androstenedione: 5–10%), conversion to
dihydrotestosterone (DHT) by 5α-reductase
occurs in the prostate.
The AR has three main regions: the
N-terminal domain (NTD), which contains
the activation function; a central DNA
binding domain; and a COOH-terminal
domain (CTD), which contains the ligandbinding region. The AR is a nuclear hormone
receptor normally bound in a complex with
multiple chaperones (heat-shock proteins,
hsps). Upon androgen binding, AR changes
its conformation, leading to nuclear
©
2012 BJU INTERNATIONAL
translocation and subsequent dimerization
with androgen response elements in the
promoter and enhancer regions of target
genes [6]. Through cytoplasmic signalling
[7–9] and recruitment of co-activator
proteins [10], target gene transcription is
enhanced, which leads to cellular
proliferation.
PROSTATE CANCER: THE ROLE OF
ANDROGEN AND AR
clones exist before the initiation of ADT is
not known [11]. With ADT, selective pressure
selects for androgen-resistant clones
preferentially to proliferate. Additional
molecular changes may cause resistant
populations of cells to become dominant,
leading to state known as castrationresistant prostate cancer (CRPC). Several
mechanisms of castration resistance have
been proposed, classified broadly as either
ligand-dependent or ligand-independent
pathways (Fig. 1). The clinical management
of patients with CRPC is challenging, as
several of these mechanisms may be
involved simultaneously in any given
patient.
LIGAND-DEPENDENT MECHANISMS OF
CASTRATION RESISTANCE
Persistent androgens despite castration
Despite castration, alterations in the
multi-step processing of androgen synthesis
and transport can provide high enough
concentrations of androgens in the tumour
microenvironment to drive tumour growth
and progression. The clinical efficacy of
secondary hormonal agents targeting the
androgen–AR axis after progression despite
castration has provided a proof of principle
Since the work of Huggins and Hodges
demonstrated regression of metastatic
prostate cancer
with surgical
‘AR is a nuclear hormone receptor normally
castration in the
bound in a complex with multiple chaperones’
1940s, manoeuvres
to deplete
that residual androgens can stimulate
androgens have remained the standard
continued tumour proliferation. Both
first-line treatment for metastatic disease.
adrenal and intra-tumoral androgens have
However, this strategy ultimately fails as
been recognised to play an essential
tumours develop mechanisms to grow
role in the development of CRPC [12].
despite low levels
of circulating
androgens.
Whether resistant
prostate cancer
‘Both adrenal and intra-tumoral androgens
have been recognised to play an essential role
in the development of CRPC’
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TSAO ET AL.
Polymorphisms in androgen conversion and
transportation have also been associated
with outcomes in CRPC [13]. Furthermore, a
recent study showed that DHT synthesis
may bypass testosterone in driving
castration resistance [14]. Taken together,
these findings highlight the multiple steps in
the pathway of androgen synthesis and
transport that can be commandeered by
tumour cells to maintain adequate levels of
androgens in the microenvironment to
support growth.
The adrenal glands have long been
recognised as a potential source of
androgen production despite surgical or
chemical castration. Early attempts to
maximize adrenal androgen blockade via
adrenalectomy had limited efficacy [15].
Subsequently, the antifungal ketoconazole, a
cytochrome P450 and 17,20-lyase inhibitor
blocking the synthesis and degradation of
adrenal steroids, was used to treat men with
CRPC confirming the importance of
extra-testicular sources of androgen
production in subsets of patients [16]. The
clinical activity of ketoconazole also
provided the conceptual, and molecular,
framework for the development of more
selective adrenal androgen inhibitors.
More recently, the importance of
intratumoral androgen production has
emerged. Several studies showed that
despite castrate levels of serum testosterone,
residual levels of testosterone remain
sufficiently elevated in the prostate cancer
microenvironment, suggesting an ‘autocrine’
pathway of androgen production may play
an important role in developing castration
resistance [12]. Selective stress from
castration causes prostate cancer to
up-regulate enzymes responsible for de novo
steroidogenesis and adrenal steroid
conversion and fuel intra-prostatic androgen
[17–21].
AR gene amplification
‘epigenetics
1582
Compared with hormone-sensitive prostate
cancer cells, up to one-third of CRPC
tumours harbour
AR gene
may play an important role in the amplification
[22–24]. Despite
development of CRPC’
castration, AR
hypersensitivity to
low levels of androgens results in continued
tumour proliferation [23,25]. In addition,
heightened AR sensitivity to DHT is
associated with increased AR expression,
stability, and nuclear localisation in CRPC
cells [26]. Therapeutic use of AR blockade
may also lead to AR over-expression and
hypersensitivity [27].
LIGAND-INDEPENDENT MECHANISMS OF
CASTRATION RESISTANCE
Conventional hormonal therapy is ineffective
when tumours grow in a truly androgen
independent manner, thus posing a major
clinical challenge, particularly as more
potent and selective androgen biosynthesis
inhibitors and AR blockers emerge. Several
mechanisms have been hypothesised to play
important roles in the development of
castration resistance including genetic
variations, epigenetic changes, and alteration
of transcriptional and translational
regulation, leading to tumour proliferation
without ligand binding.
AR mutations
Although AR mutations are uncommon in
CRPC, it has been speculated that AR is
activated by several hormones, including
progesterone, oestrogen, adrenal androgens
and metabolic by-products of DHT [28–30].
In addition, mutant ARs may also
bind AR antagonists [31,32], as well as
corticosteroids [33]. The promiscuous nature
of the mutant AR may be responsible for
the anti-androgen withdrawal syndrome,
whereby patients with progressive disease
on an anti-androgen experience a transient
disease remission simply by discontinuing
the anti-androgen. In these cases, the drug
was presumably exerting agonistic, rather
than antagonistic functions [34].
Epigenetic modification
Recent work has shown that epigenetics
may play an important role in the
development of CRPC [35]. Preclinical
models have shown that post-translational
modifications, e.g. histone modification and
DNA methylation, can lead to castration
resistance [36]. DNA hypermethylation
down-regulates the AR suppressor binding
complex leading to increased AR expression
[37], while DNA hypomethylation during
androgen deprivation increases AR signalling
in CRPC [38]. Adaptor/scaffolding protein
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2012 BJU INTERNATIONAL
TARGETING THE AR SIGNALLING AXIS IN CRPC
TABLE 1 Mechanisms of novel AR-targeted agents in clinical development
Mechanism of castration resistance
Ligand dependent
Residual androgens (adrenal + intratumoral)
AR binding (gene amplification)
Ligand independent
Constitutively active AR splice variants
Epigenetic modifications
Drug action
Novel drugs
CYP17 inhibition
17,20-lyase inhibitor
Analogue of 3β-androstanediol (d-cholesterol -x- > d-pregnenolone)
CYP17 inhibition + AR antagonist
AR antagonist + AR translocation inhibitor
Analogue of 3β-androstanediol (AR antagonist)
CYP17 inhibition + AR antagonist
Targets AR NTD
Abiraterone
TAK-700
Apoptone
TOK-001
MDV3100/ARN509
Apoptone
TOK-001
EPI-001
AR antagonist + AR translocation inhibitor
Anti-AR mRNA
HDACi
Hypomethylating agent
MDV3100
EZN4176
Panobinostat
Azacitidine
TABLE 2 Recent and on-going Phase III clinical trials of novel agents targeting AR signalling axis
Clinical Trial
COU-301
COU-302
Agent
Abiraterone
Abiraterone
No. of
patients
1000
1158
Criteria
Post-Docetaxel
Pre-Docetaxel
Primary
endpoint
OS
OS
AFFIRM
PREVAIL
NCT01193244
NCT00716794
MDV3100
MDV3100
TAK-700
TAK-700
1199
1680
1083
1454
Post-Docetaxel
Pre-Docetaxel
Post-Docetaxel
Pre-Docetaxel
OS
OS, PFS
OS, PFS
OS, PFS
Outcome/primary
completion date
Favourable OS
Favourable PFS
Study Un-blinded
Favourable OS
September, 2014
October, 2013
January, 2013
NOVEL ENDOCRINE THERAPIES
PFS, progression-free survival; OS, overall survival.
receptor for activated C kinase 1 (RACK1),
via binding to the tyrosine kinase Src,
modulates the tyrosine phosphorylation of
AR, facilitating AR translocation. This
process is ligand independent, resulting in
up-regulation of transcriptional activity in
hormonally treated prostate cancer cells
[39]. AR-mediated transcriptional activation
of several proliferation and apoptotic
pathways is critically dependent on histone
acetylation [40]. Novel therapeutic strategies
targeting these post-translational
modifications are now being investigated in
clinical trials, although early trials of these
agents have not yet shown significant
clinical activity [41,42].
AR splice variants
AR splice variants ARs have been
hypothesised to contribute to the
©
2012 BJU INTERNATIONAL
the setting of castration, co-activators such
as hsp27 [46,47], Her2Neu tyrosine kinase
[48], bcl-2 [49], and IGF-binding protein 5
[50] are up-regulated, and associated with
the development of castration resistance.
Likewise, co-repressors have been described
in AR regulation [51], with mechanisms such
as direct sequestration by DAX-1 [42], and
interruption of AR C- and N-terminal
interaction by Filamin-A [52,53].
development of CRPC [43]. Under normal
conditions, the androgen-AR complex will
translocate into the nucleus, and regulate
expression of androgen-responsive genes.
However, AR splice variant isoforms are
constitutively active, promoting tumour cell
growth independently of ligand [44]. Recent
work has shown that the AR signalling
inhibitor MDV3100 inhibits the growth of
prostate cancer cell lines harbouring some
AR splice variants [45].
AR co-activators and co-repressors
Upon binding with androgen, AR recruits
co-regulatory proteins, which include
chromatin-remodelling complexes and
transcription machinery that leads to
modulation of transcription. Several AR
co-activators have been identified as major
contributors to the development of CRPC. In
With a better understanding of the
mechanisms resulting in castration
resistance, novel therapeutic agents that
target residual androgen and the AR
signalling axis have shown significant
preclinical activity, and have rapidly entered
clinical testing (Table 1). Already, Zytiga
(abiraterone acetate) and Enzalutamide
(MDV3100) have both been shown to
improve survival in patients with CRPC
(Table 2).
Abiraterone acetate
Abiraterone acetate, an irreversible inhibitor
of cytochrome p450 complex CYP17, is an
oral agent that suppresses adrenal steroid
and intra-tumoral androgen synthesis.
Compared with its predecessor ketoconazole,
abiraterone is both more potent and
selective. In a phase I study, abiraterone
administered at multiple dose levels resulted
in marked reductions in serum testosterone
levels to <1 ng/dL, and resulted in regression
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TSAO ET AL.
of measurable disease [54]. Because
mineralocorticoids increased and resulted
in related adverse events (AEs), e.g.
hypertension, hypokalaemia, leg swelling,
adding epleronone was effective in
ameliorating these events. Responses
were also seen in patients previously
receiving ketoconazole in a second phase I
study [55].
‘evidence suggest that AR
common in CRPC and may
resistance to conventional
Two phase II trials using abiraterone
1000 mg and prednisone 10 mg daily
further demonstrated the favourable
tolerability and clinical activity in the
treatment of CRPC. In patients who were
chemotherapy naïve, 67% had a PSA level
decline of >50%, 37.5% of patients with
measurable disease
had partial
amplification is
response by RECIST
confer therapeutic criteria, and 66%
had stable disease
anti-androgens’
at 6 months [56].
However, secondary
mineralocorticoid excess resulted in
significant hypokalaemia (88%),
hypertension (40%), and fluid overload
(31%), necessitating eplerenone treatment. A
separate study evaluated patients with CRPC
that had previously received docetaxel [57].
Even in this heavily pre-treated population,
36% of the patients had >50% PSA level
declines, 18% of the patients had partial
radiographic response, and the median time
to PSA progression was 169 days.
Importantly, with the co-administration of
10 mg oral prednisone, clinical
manifestations of mineralocorticoid excess
were not observed.
Two large phase III randomised trials of
abiraterone were initiated to evaluate two
separate patient populations. COU-AA-301
randomised 1195 patients in a 2:1 ratio to
treatment with abiraterone and prednisone
in patients with CRPC who previously
received docetaxel. The combined treatment
arm showed a statistically significant overall
survival benefit (14.8 vs 10.9 months, hazard
ratio [HR] 0.65, P < 0.001) [58]. In addition,
other clinical endpoints, including time to
PSA progression (10.2 vs 6.6 months, HR
0.58, P < 0.001), radiographic progressionfree survival (5.6 vs 3.6 months, P < 0.001),
and PSA response (38% vs 10%, P < 0.001),
favoured the combined treatment arm.
Abiraterone was associated with increased
AEs, including fluid retention, hypokalaemia,
hypertension, transaminitis, and cardiac
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dysfunction in the combined treatment arm,
generally low-grade and manageable.
COU-AA-302 is a double-blinded, placebocontrolled, phase III study that randomised
1088 patients with chemotherapy naïve
CRPC to compare abiraterone 1000 mg and
prednisone 10 mg daily vs prednisone alone.
A recent press release of the interim analysis
by an independent monitoring committee
concluded that differences in radiographic
progression-free survival, overall survival,
and secondary endpoints favoured the
combined treatment arm [59].
MDV3100
Several lines of evidence suggest that AR
amplification is common in CRPC and
may confer therapeutic resistance to
conventional anti-androgens [60]. MDV3100
was developed based on preclinical activity
even in the presence of AR amplification
[61]. Compared with older generation
non-steroidal anti-androgens, MDV3100 has
greater affinity for AR, and in addition
inhibits AR nuclear translocation without
detectable agonist effects. In a phase I–II
study, escalating doses of MDV3100 were
evaluated in patients with progressive CRPC
[62]. A dose of 240 mg/day was selected for
further investigation, as higher doses
increased the risk of seizures. In the phase II
portion, administration of MDV3100
achieved PSA level declines of >50% in 56%
of patients and radiographic responses in
22% of patients. Circulating tumour cell
counts showed 49% (25/51) of patients
converting from an unfavourable count
before treatment (>5 cells/7.5 mL blood) to
a favourable count after treatment (<5
cells/7.5 mL blood) [63]. Interestingly, PET
imaging with 18F-fluoro-5α-DHT showed
decreased androgen to AR binding,
confirming the original hypothesised
mechanism of action. Two randomised,
placebo-controlled, phase III trials of
MDV3100 have been conducted, evaluating
its efficacy in patients with both pre(PREVAIL) and post-docetaxel CRPC
(AFFIRM). Recently reported interim analysis
of the AFFIRM trial, which randomised
1199 patients in a 1:1 ratio, showed
that estimated median survival was 18.4
months for men treated with MDV3100
compared with 13.6 months for men
treated with placebo (P < 0.001), with a
37% reduction in the risk of death with
MDV3100 [64].
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2012 BJU INTERNATIONAL
TARGETING THE AR SIGNALLING AXIS IN CRPC
TAK-700
Epigenetic therapy
TAK-700 is a 17, 20-lyase inhibitor that
significantly reduces adrenal and testicular
androgen levels. After showing significant in
vitro activity against prostate cancer cell
lines, a phase I/II, dose-escalation study was
initiated. TAK-700 was administered at five
dose levels, with prednisone 5 mg twice
daily. With additional patients treated at a
dose of 400 mg twice daily, dose limiting
toxicity was seen. The most common AEs
were fatigue (17 patients, three grade ≥3
with 600 mg twice a day), nausea (11
patients, one grade 3), and vomiting (seven
patients, two grade ≥3). Pharmacokinetic
analysis showed dose proportional increases
in single and multiple dose maximum
plasma concentrations of the drug (Cmax)
and the area under the concentration–time
curve (AUC0–8h). Impressively, the median
testosterone and DHEA sulphate levels
decreased from 5.5 to 0.6 ng/dL and from
50.0 μg/dL to below quantifiable levels,
respectively. All patients treated with
≥300 mg doses had a PSA level decrease
and in patients who received at least three
cycles of TAK-700 ≥300 mg, 12 (80%) had
PSA level reductions of ≥50% and four
(27%) had reductions of ≥90%. Given its
efficacy and safety, two randomised,
placebo-controlled, phase III trials have been
initiated to evaluate TAK-700 with
prednisone in patients with metastatic CRPC
in the docetaxel-naïve and docetaxel-treated
populations.
Histone deacetylase inhibitors (HDACi), via
Galeterone (TOK-001) is the first compound
modulation of HDAC activity, have a broad
to have multi-functional inhibitory activity
spectrum of epigenetic activities that have
on the AR signalling axis. In addition to
yet to be fully defined. SAHA, also known as
inhibiting CYP17, TOK-001 is also a very
vorinostat, is a USA Food and Drug
potent inhibitor of adrenal androgens and
Administration
(FDA) approved
HDACi for the
‘Hypomethylating agents have also shown
treatment of
favourable preclinical activity in the treatment
cutaneous T cell
of CRPC’
lymphoma, and has
shown anti-tumour
activity in prostate
cancer cell lines [69]. In clinical trials as
ARs. A phase I, multicentre, dose-finding
monotherapy, vorinostat did not exhibit
study in patients with chemotherapy naïve
anti-tumour activity, and was associated
CRPC was published in the American Society
with significant AEs in men with docetaxelof Clinical Oncology (ASCO) meeting in 2012
treated CRPC [41]. A phase I trial of
[73]. Patients were enrolled in cohorts from
oral panobinostat, another HDACi, with
650 to 2600 mg of TOK-001 daily, with 36
or without docetaxel, showed that the
of 49 patients completing the 12-week
dose limiting toxicities were neutropenia
treatment course. The treatment was
and dyspnea, respectively [70]. As evident
generally well tolerated, with only one
in cell lines, adding panobinostat to
severe AE considered related to TOK-001
docetaxel showed clinical activity even in
(rhabdomyolysis with acute renal failure,
patients who previously progressed on
with high dose statin use). Overall 22% of
docetaxel, providing a suggestion that
treated patients had a >50% PSA level
HDACi may overcome chemotherapy
decline, and an additional 26% had 30–50%
resistance. A phase Ib study with i.v.
PSA level declines. Consistent with lyase
panobinostat with docetaxel is currently
inhibition, increased corticosteroids and
on-going.
suppressed androgens were seen with dose
escalation.
Hypomethylating agents have also shown
favourable preclinical activity in the
ARN-509
treatment of CRPC [71]. 5-Azacitadine, an
FDA-approved agent for the treatment of
Like its structural analogue of MDV3100,
myelodysplastic syndrome, is a potent false
ARN-509 inhibits both AR nuclear
substrate
competitive
inhibitor of
‘In addition to inhibiting CYP17, TOK-001 is
methyltransferase
also a very potent inhibitor of adrenal
via its incorporation
androgens and ARs’
into DNA and RNA
during cell
replication and transcription, leading to
translocation and AR binding to androgen
silencing of promoter genes. In mouse
response elements in DNA, but with greater
models, combined treatment with castration
efficacy in prostate cancer cells with
and azacitidine delayed time to castration
over-expressed AR [74]. In a pilot phase I
resistance [72]. In 36 patients with
study, 30 patients with metastatic CRPC
chemotherapy naïve CRPC, treatment
received ARN-509 daily in nine dose
with azacitidine exhibited acceptable
escalating cohorts [75]. The most common
treatment associated AEs (four grade
grades 1–2 treatment-related AEs were
3 fatigue, two grade 3 neutropenia,
fatigue (38%), nausea (29%), and pain
and no grade 4 AEs) but only modest
(24%), with one treatment-related grade 3
in vivo clinical activity [33]. A trial of
AE (abdominal pain) at 300 mg. At 12 weeks
combined therapy with docetaxel in patients of treatment, 42% of patients have had
with chemo-naïve CRPC is currently
≥50% PSA level declines. An optimal
underway.
biological dose of 240 mg daily was selected
Apoptone
Apoptone, also known as HE3235, is a novel
synthetic analogue of 3β-androstanediol
that has shown significant preclinical
activity against prostate and breast cancer
[65]. In cell lines, apoptone binds to ARs,
resulting in the down-regulation of Bcl-2
and increased expression of caspases. In
human prostate adenocarcinoma cell lines,
apoptone decreased AR expression, and in a
CRPC xenograft suppressed tumour growth
and tumoral androgen synthesis.
Additionally, independent of CYP17
inhibition, apoptone inhibits conversion of
d-cholesterol to d-pregnenolone. An
on-going phase I/II study is exploring the
pharmacokinetics, safety, and activity of
apoptone in patients with both chemo-naïve
and chemotherapy-treated metastatic CRPC
[66–68].
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2012 BJU INTERNATIONAL
TOK-001
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TSAO ET AL.
for phase II investigation, with PSA response
at 12 weeks selected as the primary
endpoint [76].
REFERENCES
1
EZN4176
2
EZN4176, an anti-sense oligonucleotide
mRNA antagonist of AR, exhibited potent AR
and tumour inhibition in both androgen
dependent and independent xenograft
models. Upon administration, EZN-4176 is
hybridized and releases the complementary
sequences of AR mRNA, thus blocking
translation of the AR protein, leading to
inhibition of AR-induced tumour cell
growth, and promotes tumour cell apoptosis
in AR over-expressing tumour cells. This
therapy has now entered phase I clinical
testing.
EPI-001
While nearly all androgen ablative agents
target the CTD and its ligand binding region,
therapeutic effort against the NTD have
recently begun. EPI-001, a small molecule
that inhibits transactivation of the AR NTD,
has been developed as a promising agent
for the treatment of CRPC [77]. The unique
mechanism and target of this drug escape
several mechanisms of castration resistance
such as gain-of-function mutations in the
ligand-binding domain, or expression of
constitutively active splice variants. This
promising approach to targeting of the AR
has yet to enter clinical trials.
3
4
5
6
7
8
9
SUMMARY
For decades, treatment of CRPC has been
limited, resulting in dismal outcomes for
patients who failed initial hormonal
treatment. However, abiraterone and
MDV3100 have provided proof that despite
castration resistance, more potent and
selective agents targeting the androgen–AR
signalling axis can be effective. A rich
pipeline of novel therapeutic agents is
currently in various stages of preclinical and
clinical development. Continued efforts to
combat mechanisms of AR resistance will be
critical to improving prostate cancer
outcomes in the future.
10
11
12
CONFLICT OF INTEREST
13
Dr William K. Oh is a Consultant for Janssen,
Astellas, Medivation, Millenium, and receives
research funding from Millenium.
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Correspondence: William K. Oh, Mount Sinai
School of Medicine, The Tisch Cancer
Institute, 1 Gustave L Levy Place, New York,
NY 10029, USA.
e-mail: [email protected]
Abbreviations: ADT, androgen-deprivation
therapy; AE, adverse event; AR, androgen
receptor; ASCO, American Society of Clinical
Oncology; CRPC, castration-resistant
prostate cancer; CTD, COOH-terminal
domain; DHEA, dehydroepiandrosterone;
DHT, dihydrotestosterone; FDA, USA Food
and Drug Administration; HDAC(i), histone
deacetylase (inhibitors); hsp, heat-shock
protein; NTD, N-terminal domain.
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2012 BJU INTERNATIONAL