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Prostate Cancer BJUI Mini Reviews - Secondary Hormonal Therapy for Prostate Cancer: What Lies on the Horizon?
Prostate Cancer BJUI Mini Reviews - Secondary Hormonal Therapy for Prostate Cancer: What Lies on the Horizon? | BJUI Mini Reviews - Secondary Hormonal Therapy for Prostate Cancer: What Lies on the Horizon? |
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| Thursday, 06 March 2008 | ||
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BJUI Mini Reviews - In this review, novel secondary hormonal agents that are under development, which work by either inhibiting androgen synthesis or directly targeting the androgen receptor are discussed.
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![Secondary hormonal therapy for prostate cancer:
what lies on the horizon?
Nima Sharifi, William L. Dahut and William D. Figg
National Cancer Institute, Medical Oncology Branch, Bethesda, Maryland, USA
Accepted for publication 20 July 2007
testosterone. Despite advances in cytotoxic
chemotherapy, secondary hormonal
therapies are often used after the
development of castrate-resistant prostate
cancer. Secondary hormonal therapies either
lower the androgen levels further or directly
antagonize the androgen receptor in
prostate cancer cells. We discuss novel
secondary hormonal agents that are under
development, which work by either inhibiting
androgen synthesis or directly targeting the
androgen receptor.
Androgen deprivation therapy with medical
or surgical castration is generally the firstline
treatment against advanced prostate
cancer. Almost invariably, metastatic prostate
cancer overcomes testosterone depletion
and grows, despite castrate levels of
INTRODUCTION
With few exceptions, all prostate cancers
express the androgen receptor (AR). The
growth and survival of prostate cancer
initially depends on continued activation of
the AR by androgens. Therefore, androgen
deprivation therapy (ADT) has been a
mainstay of treatment against prostate
cancer. The goal with ADT is to reach castrate
levels of testosterone, i.e.
<
50 ng/dL
(1.7 nmol/L) but preferably
<
20 ng/dL
(0.7 nmol/L) [1]. ADT is the front-line
treatment against metastatic prostate cancer
and is used as an adjuvant therapy with
radiation for high risk or locally advanced
disease. In the metastatic setting the response
to ADT is usually transient, with a median
response duration of 14–20 months [2].
What has emerged from the study of
biological factors involved in the transition
from androgen-dependent prostate cancer to
castrate-resistant prostate cancer (CRPC) is
that androgen-signalling mechanisms are
reactivated. Furthermore, disease progression
continues to depend on the expression of, and
signalling through, the AR. Reactivation of
the AR in CRPC is evident in part by the reexpression
of genes that are responsive to
androgens, and by responses seen on
treatment with secondary hormonal
therapies, such as AR antagonists.
There are several mechanisms by which
androgen signalling is restored and these
converge at the level of AR itself. First, the AR
gene is amplified, leading to an increase in the
amount of AR expressed. Second, various
growth factors, cytokines and receptors
activate the AR through a phosphorylationdependent
mechanism, despite low levels of
testosterone. Third, mutations occur in the
AR, which broaden the specificity of the AR
ligand-binding domain (LBD) for recognition
of the steroids that bind and activate AR.
Fourth, there are alterations in the balance of
coactivators and corepressors of AR, which
might lead to a net gain-of-function in AR
activation. Fifth, enzymes that are involved
in the synthesis of androgens and their
precursors are up-regulated, leading to an
increase in local concentrations of androgens
in CRPC [3,4]. All of these mechanisms
indicate that the reactivation of the AR is a
central theme in the progression of CRPC and
the importance of targeting the AR as a
therapeutic method.
SECONDARY HORMONAL THERAPIES:
WHAT HAVE WE LEARNED?
Secondary hormonal therapies have two
fundamental mechanisms, both of which use
AR reactivation as a vulnerability. The first
class of agents inhibits the production of
adrenal androgens. Although there is some
evidence that corticosteroids and oestrogens
have a direct antitumour effect against
prostate cancer cells, a major effect that they
have is adrenal suppression via dampening
the hypothalamic-pituitary axis. Therefore, a
key mechanism of corticosteroids and
oestrogens entails the lowering of adrenal
androgens.
Ketoconazole enzymatically inhibits the
production of adrenal androgens. However,
ketoconazole’s inhibitory activity against
enzymes involved in steroid synthesis is not
S H A R I F I
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specific for adrenal androgens, necessitating
corticosteroid replacement to prevent the
development of adrenal insufficiency. A
recent study showed that higher
androstenedione levels are predictive of a
response to ketoconazole, further suggesting
that the mechanism of action of this drug
relates to inhibiting adrenal androgen
synthesis [5]. It is possible that measuring
androstenedione levels before treatment
could be used to select patients for therapy
with ketoconazole. Patients with low
androstenedione levels who are unlikely to
benefit from ketoconazole should then be
selected for an alternative secondary
hormonal therapy to adrenal ablation, i.e. an
agent that directly inhibits
the AR.
The second class of secondary hormonal
agents consists of drugs that directly bind to
and antagonize the AR. Although the steroidal
antiandrogens cyproterone acetate and
megestrol acetate have been used for prostate
cancer, these drugs also have effects on other
steroid receptors, leading to untoward effects
[6]. The nonsteroidal antiandrogens,
nilutamide, flutamide and bicalutamide are
more selective for the AR, with a more
desirable toxicity profile. Many clinical trials
have compared ADT alone vs ADT plus an AR
antagonist, commonly termed ‘combined
androgen blockade’ for front-line hormonal
therapy in the advanced setting. However, a
meta-analysis of 27 randomized clinical trials
of ADT vs combined androgen blockade for
metastatic or locally advanced disease
suggests that there is only a modest
improvement in survival [7]. Therefore, AR
antagonists are often used when the PSA level
increases after ADT, which might lessen the
toxicity and cost. Interestingly, PSA responses
to AR antagonists are better and more
frequent in men who have responded to ADT
or other AR antagonists than in men who
have not had responses to previous hormonal
therapies [8,9]. These observations suggest
that directing therapies at AR from varying
avenues can produce repeated responses and
that ‘androgen-independent’ prostate cancers
still depend on the AR, particularly if they
were initially responsive to hormonal therapy.
ABIRATERONE
Abiraterone acetate suppresses adrenal
androgen synthesis by inhibiting 17
α
hydroxylase and C17, 20-lyase. In theory, the
more focused and specific inhibition of the
androgen synthetic pathway with abiraterone
than with ketoconazole would be less likely to
require corticosteroid replacement for adrenal
insufficiency. A phase I trial of abiraterone in
16 patients with metastatic or nonmetastatic
CRPC was completed recently [10]. Only
two of 16 patients required corticosteroid
replacement. Interestingly, the enzyme
inhibitory spectrum of abiraterone led to
a 6.7-fold median increase in the
mineralocorticoid deoxycorticosterone.
Furthermore, four patients developed
hypertension, probably due to
mineralocorticoid excess, that was treated
with aldosterone antagonists. There were
declines of
>
50% in PSA level in seven of 14
patients, including five of nine who had been
previously treated with ketoconazole. A
second phase I study of abiraterone was
reported in patients with CRPC, not previously
treated with ketoconazole [11]. Nine of 16
patients had declines
>
70% in PSA level and
hypertension was again reported in that
study.
NOVEL CLASSICAL AR ANTAGONISTS
One way in which prostate cancer overcomes
treatment with classical AR antagonists is
with mutations in the LBD, which convert
antagonist activity to agonist activity, often
leading to declines in PSA level after
withdrawal of antiandrogen therapy [12,13].
The first mutation in the AR LBD was found in
the LNCaP prostate cancer cell line. This T877A
point mutation causes AR activation with
cyproterone acetate, nilutamide and
hydroxyflutamide. In addition, the T877A
mutation allows activation by progesterone
and oestradiol [14]. Novel drugs are needed
for treating prostate cancers that have
acquired such AR mutations and that have
overcome treatment with the clinically
available AR antagonists.
Insights into designing novel AR antagonists
can be gleaned from studies in structural
biology. A major limitation is that no
antagonist bound to the wild-type AR has
been determined by X-ray crystallography.
However, the crystal structure of bicalutamide
bound to the mutant W741L AR, that confers
agonist activity to bicalutamide, has been
determined [15]. This mutation might also
be responsible for some cases of the
antiandrogen withdrawal syndrome. The
bicalutamide complex with W741L AR has
a similar overall protein fold, resembling
the wild-type AR complex with
dihydrotestosterone. This is not surprising,
given the agonist activity of bicalutamide
with this mutant AR. The structural basis of
how bicalutamide interacts with the mutant
domain of AR reveals clues to how mutations
in AR give rise to AR antagonist resistance.
Novel classes of AR antagonists are being
developed which have binding affinities for
wild-type AR that are over 10 times greater
than that of bicalutamide, which of the
clinically available nonsteroidal AR
antagonists has the highest affinity for AR
[16]. Importantly, some of these compounds
also potently bind to and antagonize AR
with mutations, such as T877A and other
mutations in the AR LBD. BMS-641988 is a
novel AR antagonist which is in early-phase
clinical trials [6]. AR antagonists with high
potency, a novel chemical structural basis and
unique resistance profiles will eventually offer
patients with prostate cancer a wider array of
treatment options.
NON-CLASSICAL AR ANTAGONISM
The AR directly associates with steroid
receptor coactivators and steroid receptor
corepressors. AR agonists such as
dihydrotestosterone induce an association
with steroid receptor coactivators and
dissociation with corepressors, while AR
antagonists have the opposite function. For
example, bicalutamide induces AR nuclear
translocation and DNA binding to the PSA
enhancer, but its inability to recruit steroid
receptor coactivators makes it unable to elicit
AR-dependent transcription [17]. The critical
requirement of steroid receptor coactivators
for steroid receptor function is illustrated by
the fact that steroid receptor coactivator
‘knockout’ mice have decreased weights of
steroid responsive organs, such as prostate
[18]. Disrupting the interaction between AR
and steroid receptor coactivators that are
required for AR function therefore is a
potential method to antagonize the AR. The
AR is unique among other steroid receptors in
that it has two families of coactivators, SRC
and ARA [19]. However, a problem in the
discovery and development of inhibitors of
protein–protein interactions is the difficulty
in finding a cleft or pocket in which a small
molecule can bind with practical affinity.
Some investigations are focused on
identifying peptide inhibitors of the
interaction between AR and coactivators [19].
S E C O N D A R Y H O R M O N A L T H E R A P Y F O R P R O S TAT E C A N C E R
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Another protein that interacts with AR is
heat-shock protein (HSP)-90. HSP90 is
required for appropriate protein folding and
for protein maturation. HSP90 inhibitors such
as geldanamycin, 17-AAG and 17-DMAG
cause AR protein degradation. Targeting AR
with HSP90 inhibitors is one strategy that is
being pursued and some of these compounds
are in early clinical trials [6]. However, the
function of HSP90 is not specific for AR,
which might be one reason why some
members of this class have a myriad of
toxicities.
The best pocket in AR for drug binding is the
LBD. Another strategy would be to take
advantage of the LBD and to use this for
a non-classical method of antagonism.
Creating an AR ligand that has an
independent functional moiety would allow a
therapy to be specifically directed at AR.
Colchicine-cyanonilutamide (CCN) is a
compound that joins the tubulin-binding
function of colchicine and the AR-binding
capacity of cyanonilutamide through a rigid
linker [20]. A bifunctional compound such
as this would provide several potential
mechanisms of AR antagonism. First,
extending a bulky moiety such as colchicine
outside the ligand-binding pocket of AR could
block protein coactivators from interfacing
with the AR, in a manner that is distinct from
classical AR antagonists. Second, linking a
toxic moiety to an AR ligand could provide
specificity against AR-expressing cells, e.g.
prostate cancer. Third, steroid receptor
nuclear import is tubulin-dependent and
disrupting this with colchicine, which only
binds the soluble tubulin heterodimer, might
disrupt this process. Fourth, the only form of
chemotherapy that gives a survival benefit in
prostate cancer is a tubulin-binding drug.
The LBD of steroid receptors reflects the
hydrophobic nature of steroid ligands. Steroid
ligands bind deep within steroid receptors and
are not readily accessible to the surface of the
protein. Creating a bifunctional molecule that
fits in a steroid receptor such as AR, and that
has a moiety that extends outside this protein
without losing binding affinity to the steroid
receptor, is fraught with potential difficulties.
Surprisingly, despite the bulky colchicine
moiety, CCN binds to AR with only a 10-fold
lower binding affinity than hydroxyflutamide,
which is the active form of flutamide.
Structural modelling of CCN bound to AR
shows two potential configurations of how
this ligand stably fits into the LBD. Both of
these configurations show that the linker
follows a channel through AR and permits the
preservation of binding by extending the
colchicine moiety just outside the AR. CCN
kills CRPC cells better than the combination of
colchicine and nilutamide [20]. Compounds
designed with AR-targeting bifunctional
intent and novel mechanisms of AR
antagonism might lead to new therapies for
CRPC.
The interaction between AR and the
androgen-response element DNA-binding
domain is a potential point of intervention in
CRPC. A similar strategy has been supported
with a compound that inhibits the interaction
between the oestrogen receptor (ER) and DNA
in a preclinical model of breast cancer [21].
This strategy provides specificity to targeting
the ER. In addition, this electrophilic
compound, which targets the zinc-finger
domain of the ER, inhibits the interaction
between ER and receptor coactivators.
CONCLUSION
Secondary hormonal therapies for prostate
cancer often lead to declines in PSA level and
disease control in CRPC. These therapies, that
either decrease androgen synthesis or directly
target the AR, take advantage of AR
reactivation in CRPC. New drugs with novel
mechanisms of down-regulating AR function
are needed that can overcome resistance to
standard secondary hormonal therapies.
Abiraterone acetate and BMS-641988 are two
drugs in early-phase clinical trials that appear
to be promising. Preclinical studies with
compounds that are non-classical AR
antagonists and that target the interaction
between the AR and protein coactivators,
AR and DNA, or other mechanisms with
independent functional moieties, hold the
promise to make further progress against
CRPC.
ACKNOWLEDGEMENTS
This research was supported in part by the
Intramural Research Program of the NIH, and
the Center for Cancer Research, National
Cancer Institute.
CONFLICT OF INTEREST
None declared.
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Correspondence: Nima Sharifi, Medical
Oncology Branch, National Cancer Institute,
Building 10, Room 5A01, Bethesda, Maryland
20892, USA.
e-mail:
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Abbreviations:
AR
, androgen receptor;
ADT
,
androgen-deprivation therapy;
CRPC
,
castrate-resistant prostate cancer;
LBD
,
ligand-binding domain;
HSP
, heat-shock
protein;
CCN
, colchicine-cyanonilutamide;
ER
,
oestrogen receptor.](http://urotoday.com/images/stories/bjui_feb2008_cover.gif)
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