SPECIAL FOCUS y Hormones in breast and prostate cancer Editorial

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The major role of androgens in prostate

cancer and the need for more
efficient blockade
Expert Rev. Endocrinol. Metab. 6(3), 313–316 (2011)

Fernand Labrie
Department of Molecular
Medicine, Laval University,
Québec City, QC, Canada
and
College of Medicine, Al-Imam
Mohammed Ibn Saud Islamic
University, Riyadh,
Saudi Arabia
Tel.: +1 418 652 0197
Fax: +1 418 651 1856
flabrie@attglobal.net
“Prostate cancer is the most sensitive of all cancers to hormone
therapy. Every effort should therefore be made to take
advantage of this unique characteristic.”
Although improvements in surgery and
radiotherapy have also occurred, National
Cancer Institute data from 2.1 million
patients with cancer in the USA between
1975 and 1995 have led to the conclusion
that “cancer-fighting drugs improved sur-
vival rates, especially for cancer of the pros-
tate, where drug innovations have been the
greatest”  [1] . In prostate cancer, the most
important drugs have been gonadotropin-
releasing hormone (GnRH) agonists [2]
and pure anti-androgens permitting the
administration of a pure anti-androgen
combined with medical or surgical cas-
tration (combined androgen blockade
[CAB]), at the start of treatment [3] .
However, despite significant improvements
in diagnosis and treatment, prostate cancer
remains the second most common cause of
death after lung cancer in American men.
Very high sensitivity to androgens
Prostate cancer is the most sensitive of all
cancers to hormone therapy. Every effort
should therefore be made to take advantage
of this unique characteristic. In 1980, it was
discovered that medical castration is easily
achieved in men by chronic administration
of GnRH agonists [2] . This is a unique dis-
covery in medicine since, for the first time,
a completely unexpected inhibitory effect
was observed using a superactive stimu-
latory molecule (GnRH agonist), which
was expected to lead to a long-term and
potent stimulation of testicular functions.
This discovery is particularly important for
patients with localized prostate cancer who
need a well-tolerated therapy for long-term
use. In fact, GnRH agonists are psycho-
logically and medically much more accept-
able to men with prostate cancer than
orchidectomy or high doses of estrogens;
accordingly, GnRH agonists were rapidly
adopted worldwide to achieve medical cas-
tration [4] . A meta-ana­lysis that combined
data from several studies involving approxi-
mately 5000 men concluded that the risk of
dying from prostate cancer within 10 years
decreased by a third if blockade of testicular
testosterone secretion was started immedi-
ately after diagnosis rather than once the
disease had progressed [5,6] .
Comparable amounts of androgens
made in testicles & peripheral tissues
A lthough GnR H agonists rapidly
became the standard treatment world-
wide to eliminate testicular androgens,
early biochemical studies using human
prostatic tissue demonstrated that andro-
gens were also synthesized in the prostate
from dehydro­epiandrosterone (DHEA),
a precursor of sex steroids produced by
the adrenal glands. In fact, approximately
40% of androgens remain in the prostate
after castration alone [3,7] . Consequently,
a further improvement in survival over
castration alone should logically be
expected after treatment with CAB. In
fact, provided that treatment is initiated

Keywords : androgens • antiandrogens • enzyme inhibitors • GnRH agonists • intracrinology

• prostate cancer

www.expert-reviews.com 10.1586/EEM.11.5 © 2011 Expert Reviews Ltd ISSN 1744-6651 313

 Editorial Labrie
immediately after diagnosis in patients with localized or locally
advanced disease and is continued for at least 7 years without
interruption, CAB can achieve long-term control or potentially
cure prostate cancer in at least 90% of cases, as judged by
no increase in serum prostate-specific antigen (PSA) within
at least 5 years after stopping CAB administered up to 9 years
previously [8] .
“...the risk of dying from prostate cancer within
10 years decreased by a third if blockade of
testicular testosterone secretion was started
immediately after diagnosis rather than once the
disease had progressed.”
Physicians often erroneously believe that androgen blockade
should not be administered early in prostate cancer because resist-
ance to treatment is very likely to develop, thus ‘saving’ androgen
blockade for use at a later stage of the disease. The fact that this
belief is incorrect is proven by the observation that resistance to
CAB develops extremely rarely in patients with localized pros-
tate cancer [8–10] . In fact, resistance to CAB is a problem specific
to metastatic disease and is not found with CAB started at the
localized stage.
In advanced prostate cancer, a series of clinical trials have dem-
onstrated that CAB has several advantages over castration alone.
These advantages include a higher proportion of patients with
complete and partial responses to treatment, improved control of
pain associated with metastatic disease, and longer disease-free
and overall survival [11–14] . In fact, the combination of a pure anti-
androgen (flutamide, nilutamide or bicalutamide) with a GnRH
agonist was the first treatment that was shown to prolong life in
patients with advanced prostate cancer [3,11] .
Resistance to treatment is a usual finding in
metastatic disease
When androgen blockade is started at the metastatic stage, dis-
ease progression always occurs. Such resistance to treatment has
generally been viewed as the end of the therapeutic role of andro-
gen blockade. However, early preclinical [15] and clinical [16] data
clearly indicated that responsiveness to androgens remains present
at all stages of prostate cancer, thus offering a major opportunity
to develop effective hormonal therapies for these patients.
It has been known for approximately 40 years that patients
with castration-resistant prostate cancer (CRPC) can respond to
further androgen blockade. More recently, it has been observed
that a large proportion of patients experience a paradoxical posi-
tive clinical response upon a simple change of the anti-androgen,
with a decrease in serum PSA of >90% in 47% of patients [17–19] .
Two possible explanations exist for this benefit of anti-androgen
withdrawal: the development of androgen hypersensitivity or a
response to low androgen levels due to hypersensitivity of the
androgen receptor [15,20] or intracellular changes that cause the
anti-androgen to act as a partial agonist because of an increase
in androgen receptor levels as discussed later.
314
Mechanisms of resistance to androgen blockade
The traditional therapeutic approach for CRPC patients deserves
re-evaluation following the observations of elevated andro-
gen receptor levels, increased local androgen biosynthesis and
decreased androgen inactivation in the prostate [21–23] .
The prostate contains the enzymes that convert DHEA into
active androgens thus explaining why intraprostatic dihydro­
testosterone remains at sufficiently high levels to activate the
androgen receptor following castration [24–26] . Moreover, ani-
mal  [27] and human fetal [28] studies indicate that DHEA and
androgens are produced in non­gonadal tissues other than the
adrenal glands. Consequently, in analogy with other peripheral
tissues, DHEA could be potentially synthesized from cholesterol
in the prostate. These potential alternative sources of androgens
derived from DHEA, and possibly from cholesterol, could be
implicated in the development of CRPC by acting directly in
the prostate.
Need for more potent anti-androgens & inhibitors of
androgen biosynthesis
Although anti-androgens that have pure antagonistic activity at
the androgen receptor level (flutamide, bicalutamide and niluta-
mide), are available and have shown major benefits in prostate can-
cer therapy [3,4,8,9,11–14,16,17,29–31] , the affinity of these compounds
for the androgen receptor is low [32] . Consequently, the currently
available anti-androgens cannot induce maximal apoptosis or cell
death in prostate cancer tissue.
There is therefore a clear need for novel pure anti-androgens
that have higher affinity for the human androgen receptor in
order to take full advantage of the particularly high sensitivity
of prostate cancer to androgens. Highly potent anti-androgens
should be able to neutralize the low levels of androgens that
remain during treatment with the presently available agents,
especially GnRH agonists combined with flutamide, bicaluta-
mide or nilutamide, and could even block the activity of recep-
tors with a mutated ligand-binding domain that respond to low
intracellular androgen levels [33] . In this context, positive clini-
cal data on serum PSA have been obtained in studies with the
new anti-androgen MDV3100 in patients with CRPC where a
decrease in serum PSA has been observed [34] . No other novel
anti-androgen has yet provided clinical data of efficacy.
“...real hope exists that the development of more
potent androgen receptor antagonists and specific
inhibitors of androgen biosynthesis could further
improve the survival and quality of life of patients
with prostate cancer.”
Moreover, promising data have been obtained with abiraterone,
an inhibitor of 17a-hydroxylase (CYP17A1) [35,36,101] . However,
such results should be compared with the addition of flutamide
to GnRH agonists in patients with CRPC in whom a clinical
response lasting for 24 months on average was observed in a third
of patients [16] .
Expert Rev. Endocrinol. Metab. 6(3), (2011)
 The major role of androgens in prostate cancer & the need for more efficient blockade Editorial

Conclusion
In the past, clinicians and researchers did not appreciate that
prostate cancer cells could make their own androgens [3,24,37,38]
by the mechanisms of intracrinology [38] . However, this ‘blind
spot’ is no longer justifiable since this knowledge has now been
available for at least 25 years [3,38] . Consequently, when androgen
blockade is indicated as a first-line treatment, CAB should always
be used instead of performing stepwise blockade of androgens,
namely castration followed by CAB, when CRPC had sufficient
time to develop. This is the approach usually followed today,
despite the widely available scientific evidence for the presence of
two sources of androgens, namely the testicles and the adrenals.
In addition, clear evidence indicates that CAB should be
administered to those patients who have previously been unfor-
tunately treated with castration or an anti-androgen alone. Data
obtained in patients with metastatic prostate cancer, especially
in those with CRPC, confirm that the development of resistance
to a specific mode of androgen blockade does not mean that
androgens and the androgen receptor no longer drive cancer cell
proliferation. In particular, castration does not abolish the stimu-
latory effect of the approximately 40% of androgens made locally
in the prostate. Study of the mechanisms of androgen resistance
indicates both increased androgen receptor levels and contin-
ued local androgen biosynthesis. In patients with CRPC, for
example, further treatment with an anti-androgen or a blocker
of androgen biosynthesis can provide notable clinical benefits.
Even the few months of life added by currently available treat-
ments for patients with CRPC are both medically and socially
important, and real hope exists that the development of more
potent androgen receptor antagonists and specific inhibitors of
androgen biosynthesis could further improve the survival and
quality of life of patients with prostate cancer. This approach could
well permit a series of successive significant positive response – up
to fourth- and fifth-line treatments, as is observed in breast can-
cer – before the need to move to nonhormonal agents, such as the
cancer vaccine sipuleucel T and chemo­therapeutic agents, such
as docetaxel and cabazitaxel, which carry much higher risks of
toxicity. However, we should not forget that maximal benefits
are expected when maximal androgen blockade is applied as first
treatment early in the evolution of the disease. In order to achieve
this goal of early diagnosis of prostate cancer, prescreening with
PSA is required [39] .
Financial & competing interests disclosure
Fernand Labrie is President and CEO of Endorecherche Inc. (Quebec,
Canada), which owns received and pending patents on antiandrogens and
performs research on this subject. The author has no other relevant affilia-
tions or financial involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.

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