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UROLOGY BOARD REVIEW MANUAL
STATEMENT OF
EDITORIAL PURPOSE
The Hospital Physician Urology Board Review
Manual is a peer-reviewed study guide for
residents and practicing physicians preparing
for board examinations in urology. Each
manual reviews a topic essential to the current
practice of urology.
PUBLISHING STAFF
Mechanisms of Disease
Progression and Treatment
Resistance in Prostate Cancer
Contributor:
Karen E. Knudsen, PhD
Professor of Cancer Biology, Urology, & Radiation Oncology, Kimmel
Cancer Center, Thomas Jefferson University, Philadelphia, PA
PRESIDENT, GROUP PUBLISHER
Bruce M. White
SENIOR EDITOR
Robert Litchkofski
EXECUTIVE VICE PRESIDENT
Barbara T. White
Table of Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
EXECUTIVE DIRECTOR
OF OPERATIONS
Jean M. Gaul
Role of the Androgen Receptor in Prostatic
Adenocarcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Therapy Resistence and Progression to CastrationResistant Prostate Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . 5
Advances in Targeting Hormone Therapy–Resistant
Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
NOTE FROM THE PUBLISHER:
This publication has been developed
without involvement of or review by
the Amer­ican Board of Urology.
Board Review Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
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Urology Volume 15, Part 2 1
UROLOGY BOARD REVIEW MANUAL
Mechanisms of Disease Progression and
Treatment Resistance in Prostate Cancer
Karen E. Knudsen, PhD
INTRODUCTION
Prostatic adenocarcinoma is a major health challenge in most Western countries, and the means to
durably treat disseminated disease have been elusive.
The pioneering work of Huggins and Hodges in the
1940s established the importance of androgens for
the growth and development of prostate cancer,1–3 and
targeting this reliance on androgen action remains the
conceptual basis of treatment for advanced disease.4–9
Antiandrogen strategies are initially effective in the majority of patients. However, recurrent disease arises due
to restoration of androgen activity and/or androgen
receptor (AR) signaling, and it is this stage of disease
that has proven difficult to treat. This article reviews the
underlying basis of disease progression and treatment
resistance in prostate cancer, with a focus on the molecular mechanisms that govern recurrent androgen
activity and AR signaling in the clinical setting.
EPIDEMIOLOGY
As of 2011, prostate cancer remains the second
leading cause of cancer death in men in the United
States and the most frequently diagnosed noncutaneous malignancy.10 It is predicted that in 2012 over
215,000 American men will receive a new diagnosis
of prostate cancer; unfortunately, approximately 15%
of patients will have metastatic lesions at initial diagnosis,11 and over 30,000 will die of their cancer. Correct identification of truly organ-confined disease is
of significant benefit, since early-stage disease can be
effectively treated through surgical resection or via
radiation therapy. However, treatment failure is common, and a significant fraction of patients (up to 40%)
will develop biochemical relapse and require treatment
for non–organ-confined disease.4,9,12 Although the underlying basis remains incompletely defined, prostate
cancers that spread beyond the primary site are largely
refractory to standard chemotherapeutic agents and
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antimitotics, and no curative treatment regimen has
yet been defined for advanced prostate cancer. As such,
determining the basis of disease progression is an area
currently under intensive study, and translational discoveries have recently led to approval of promising new
therapeutic agents to treat advanced disease.
ROLE OF THE ANDROGEN RECEPTOR IN
PROSTATIC ADENOCARCINOMA
OVERVIEW OF AR FUNCTION AND REGULATION
Prostatic adenocarcinomas are noted for their exquisite dependence on and addiction to androgen signaling for growth and survival.4,13,14 Testosterone is the most
abundant circulating androgen in the human adult
male, and in the context of a normal prostatic epithelial
cell or prostatic adenocarcinoma cell, testosterone is
converted to the potent androgen dihydrotestosterone (DHT) through the action of a resident enzyme,
5α-reductase.15 The biological activity of both androgens
is mediated through their binding to their cognate receptor, the AR, which serves as a ligand-dependent transcription factor. A part of the nuclear receptor superfamily of transcription factors, AR contains conserved
C-terminal functional domains (hinge, DNA-binding
domain, and the ligand-binding domain) but harbors
a unique N-terminal region.16–20 Distinct from many of
the other nuclear receptors, the N-terminal region supports the main transcriptional transactivation function
of the receptor (activation function 1, AF1).18,19 Prior to
ligand binding, the AR is present diffusely throughout
the cytoplasm and nucleus, and remains inactive due
to association with inhibitory chaperone molecules
such as heat-shock proteins. Upon ligand (testosterone
or DHT) binding, heat shock proteins are released.
Subsequently, the receptor undergoes conformational
changes that promote transcriptional transactivation
functions, forms a homodimer, and rapidly translocates
to the nucleus. Activated nuclear AR homodimers bind
to DNA at specific DNA sequences (androgen response
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Figure 1. Androgen receptor function and targeting in prostate cancer progression. The androgen receptor (AR) consists of 3 domains
(the DNA-binding domain [DBD]; a hinge region [H]; and a C-terminal ligand-binding domain [LBD]) and a unique N-terminal domain that
contains the principle transactivation domain (TAD). Ligand (indicated by circles: testosterone [T] or dihydrotestosterone [DHT]) binding
induces homodimerization and rapid nuclear translocation. Active homodimers bind DNA at androgen responsive elements (ARE) within
the regulatory regions of target genes, recruit coactivators (Co-Act), and induce a gene expression program that includes activation of
prostate-specific antigen (PSA). The AR C-terminal domain is targeted clinically in patients with non–organ confined disease by the use of
androgen ablation and direct AR antagonists (indicated by triangles).
elements, or AREs) at the regulatory regions (enhancers and promoters) of target genes and therein recruit
a series of coregulators that assist in promoting contextspecific and cell–type specific gene expression programs
(Figure 1).
In the context of a normal prostate gland, activated AR initiates a gene expression program that is
decidedly prodifferentiative, as a number of model
systems have demonstrated that AR is required for
development and maintenance of differentiated luminal epithelia.21 Moreover, patients with germline
mutations in 5α-reducatase or AR that compromise
receptor activity fail to develop a functional prostate.22,
23
Differentiated prostatic epithelia serve to produce
and secrete a number of proteases that support prostate function; one of these proteases is encoded by
the KLK3 gene and produces a protein marker of
clinical relevance for prostate cancer, prostate-specific
antigen (PSA.)24–27 PSA secretion is a hallmark of both
prostatic epithelia and prostatic adenocarcinoma cells,
which retain some salient features of luminal epithelia.
A large body of evidence has demonstrated that KLK3/
PSA gene expression is under stringent control of AR,
and is arguably one of the best-characterized AR target
genes. In both normal prostatic epithelia and prostatic
adenocarcinomas, activated AR binds to enhancer and
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promoter regions of the KLK3 locus and acts as a catalyst to recruit both coactivators that facilitate chromatin
opening and basal transcriptional machinery to induce
gene expression.28–30 Since the resulting protein product is secreted into the sera, PSA levels can serve as a
monitor of the number of cells of prostate origin that
have the AR pathway engaged. As such, PSA levels are
routinely utilized as a means to detect prostate cancer
growth and progression.
Despite the commonality of KLK3/PSA as a gene
under AR regulation in both normal and cancer cells
of the prostate, the biological outcome of AR activation is distinct in the 2 cell types. Whereas AR serves
a prodifferentiative role in normal adult prostatic
epithelia, a multitude of investigations demonstrate
that AR harbors cell-autonomous pro-proliferative and
prosurvival functions in prostatic adenocarcinoma.31–34
Further, recent findings suggest that the profile of
genes controlled by AR continues to change as a function of disease progression, such that AR is “rewired” in
therapy-resistant disease to promote gene expression
events that support aggressive tumor phenotypes.35 As
preclinical modeling and clinical investigation strongly
support the contention that recurrent AR activity after
therapeutic intervention drives progression to the lethal stage of disease, it is critical to define the means
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PCa cell
HORMONE THERAPY
GnRH agonists and antagonists
Anti-androgens
SNARE-1
Bicalutamide
Nilutamide
Flutamide
Cyperaterone
acetate
MDV3100
PSA
Proliferation
TMPRSS2
Survival
Selective pressure
Cell death
Tumor Regression
Cell cycle arrest
Abiraterone
acetate
EPI-001
DEREGULATION
Amplification
Overexpression
ABERRANT
MODIFICATION
ALTERNATIVE
SPLICING
COFACTOR
MUTATION
PERTURBATION Gain of function
GF, cytokine pathways
Src
Dasatinib
Constitutively active
CoACT gain
CoR loss/dismissal
INTRACRINE
ANDROGEN
SYNTHESIS
RESTORED AR ACTIVITY
Rising PSA (biochemical failure)
CRPC tumor growth
Mechanisms of
adaptation
CRPC
development
Therapeutic Failure
Figure 2. Mechanisms of androgen receptor (AR) reactivation in the transition to hormone therapy resistance. Tumors evade hormone
therapy through the restoration of AR activity, which can be achieved through multiple mechanisms. Agents designed to target hormone
therapy–naïve and recurrent AR activity are shown in red.
by which AR activity is restored and/or altered in
advanced disease, and to develop means to effectively
treat this late stage of cancer.
TARGETING THE AR IN DISSEMINATED DISEASE
Suppression of androgen synthesis through the use
of gonadotropin-releasing hormone agonists currently
remains the first line of therapeutic intervention for disseminated prostate cancer.4 These regimens function to
deplete the AR of ligand and thereby suppress receptor
activity. Cooperative strategies are often employed in concert, wherein direct AR antagonists such as bicalutamide,
flutamide, or nilutamide are given as adjuvant therapies.
In general, these agents compete with testosterone or
DHT for binding to the AR ligand-binding domain,
further suppressing receptor activity. AR antagonists
have a second actively suppressive function in that the
receptor perceives these first-generation antagonists as
a ligand that promotes nuclear entry and DNA binding.
Once bound to DNA, bicalutamide-bound receptors
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can induce recruitment of corepressor molecules such
as NCoR (nuclear corepressor) and SMRT (silencing
mediator of retinoic acid and thyroid hormone receptors) to actively suppress transcriptional transactivation.36
Whether used in isolation or in combination with AR
antagonists, androgen-suppression strategies are highly
effective at blocking AR activity, as evidenced by a marked
reduction in detectable serum PSA in patients undergoing treatment.37,38
At the cellular level, androgen deprivation leads to
either cell death or cell cycle arrest,31,39 and tumor remission is observed. Unfortunately, within 2 to 3 years’
median time, recurrent tumors form that can survive
and proliferate in the castrate environment, a condition
referred to as castration-resistant prostate cancer (CRPC). It
has long been observed that rising PSA (referred to as
“biochemical failure”) almost invariably heralds development of a recurrent tumor that can be detected by radiographic or other means, providing some of the first evidence that the AR pathway has been reactivated despite
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the maintenance of therapeutic intervention. Indeed,
subsequent clinical investigation and modeling of the disease confirmed that restoration of AR activity can occur
through multiple mechanisms (Figure 2), and recurrent
AR activity appears to be the major means through which
resistance to first-line therapeutic intervention occurs.
As such, recurrent AR activity is considered to be critical
for progression to the castration-resistant stage.
THERAPY RESISTANCE AND PROGRESSION TO
CASTRATION-RESISTANT PROSTATE CANCER
Restoration of AR activity despite the maintenance
of androgen deprivation therapy (ADT) is thought to
be the major mechanism of CRPC development.4,5,13
Investigation of the underlying mechanisms continues
to be an area of productive discovery that has led to
the development of new modes of therapeutic intervention. At present, at least 5 major mechanisms have
been identified in the clinical setting and validated in
preclinical models that can account for promoting ARdependent disease progression to CRPC.
AR DEREGULATION
It has long been recognized that elevated AR levels
predict significantly increased risk of death from prostate cancer,40 and, in models of human disease, mimicking AR deregulation is sufficient to confer resistance
to ADT. For example, elegant studies from Sawyers
and colleagues demonstrated that overexpression of
the gene encoding AR allowed tumor growth after
androgen deprivation in vitro, and rendered human
tumor resistant to castration in xenograft models.41
As would be expected, AR overexpression also resulted
in marked upregulation of known target genes in
human cells, including PSA. The biochemical means
by which excessive AR expression leads to restored
activity is thought to be centered on the fact that the
receptor retains some basal activity in the castrate environment, and that overproduction of the protein is
sufficient to induce AR gene expression programs to
the threshold level required to induce tumor growth
and survival. In addition, it should be considered that
even in the case of effective GnRH agonist–dependent
castration, circulating androgens derived from the
adrenal gland are not altered by this therapy, and is it
known that elevations in AR can sensitize tumor cells to
low levels of ligand.41,42 Thus, precursors derived from
the adrenal glands or other tissues, and/or intracrinederived androgens (discussed below) are hypothesized
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to cooperate with high AR levels to sensitize cells to the
pro-tumorigenic effects of residual androgens.43
In the clinical setting, a significant fraction of CRPC
tumors exhibit significant AR elevation, which can be
attributed to either amplification of the locus encoding the AR gene or to amplification-independent
molecular alterations that lead to overexpression of the
AR gene.44–46 AR amplification has been reported in up
to 30% of CRPCs, suggesting that this is a major means
of CRPC development. Amplification-independent
mechanisms of AR upregulation can occur in human
disease as a result of variant pro-tumorigenic genetic
alterations, including loss of the purine-rich element
binding (Pur)-alpha corepressor or upregulation of
the transcription factor lymphoid-enhancing factor
1 (LEF),47,48 both of which impinge upon AR gene
expression. Recently, an unexpected link between the
retinoblastoma tumor suppressor (RB) and AR expression was identified; as part of RB function as a negative
regulator of transcription, it was discovered that RB
assembles repressor complexes that dampen AR gene
expression.42 Loss of RB, which was shown to occur
with high frequency in human CRPC, proved sufficient
through molecular modeling to promote AR overexpression sufficient to induce CRPC both in vitro and
in vivo. Accordingly, further investigation of human
CRPC showed that not only is RB loss overrepresented
in CRPC, but this genetic alteration also inversely
correlates with excessive AR expression. These findings identify suppression of AR expression as a major
means through which the RB tumor suppressor serves
to protect against the transition to CRPC. It is clear
that high-level AR expression and output together are
sufficient to promote resistance to first-line therapeutic
intervention, and that multiple genetic alterations can
induce AR levels sufficient to drive CRPC.
POST-TRANSLATIONAL MODIFICATION AND AR
COFACTOR ALTERATIONS
While overexpression of the endogenous, wild-type
AR can promote treatment resistance, an emerging
body of evidence strongly suggests that altered posttranslational modification of the AR and/or aberrant
expression of AR cofactors can facilitate this process.16,49
The receptor is known to be modified by phosphorylation (both serine/threonine and tyrosine), acetylation,
sumoylation, and ubiquitination, and as has been
extensively reviewed, these modifications are major
modulators of AR activity.50–53 Selected modifications
have been linked to growth factor pathways relevant to
prostate cancer, suggesting that targeting the enzymes
that are responsible for post-translational modification
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may be of possible clinical benefit. For example, it is
known that the Src kinase induces tyrosine phosphorylation of AR, and that this phosphorylation event can
promote castration-resistant AR activity. The relevance
of this event was further demonstrated through investigation of human tumor specimens that revealed
CRPC-specific upregulation of the Src-sensitive phosphorylation event. Importantly, dasatinib (a known Src
inhibitor) is in clinical trial to assess its impact on solid
tumors, including prostate cancer,54,55 and early findings suggest that this approach may prove effective at
suppressing AR activity.56,57 There is a current emphasis
in the field on identifying the complex network of enzymes that govern AR post-translational modifications
of clinical relevance, and determining whether these
pathways could serve as a valid target for therapeutic
intervention. Similar interests are directed toward
understanding the role of AR cofactors in treatment
resistance. Given the observation that alterations which
promote excessive AR expression and activity underlie
the transition to CRPC, it is not surprising that alterations in transcriptional cofactors that modulate AR
function on chromatin have also been observed in the
clinical setting. These alterations typically involve loss
or dismissal of corepressors that normally serve to keep
AR activity in check58 or upregulation of coactivators
that facilitate AR function.16 The basis for these alterations can be genetic; for example, loss of the NCoR1
corepressor and gain of the SRC2 coactivator are overrepresented events in human CRPC.59 By contrast, AR
cofactor alterations can occur as a result of changes
in the tumor microenvironment. Exemplifying this,
elegant studies showed that macrophage infiltration
into the tumor microenvironment results in a signaling cascade that causes dismissal of NCoR1 from the
AR complex (thus triggering enhanced AR function
sufficient to promote resistance to AR bicalutamide).60
These findings suggest that AR cofactors modulate the
response to therapeutic intervention, and that these
events should be considered when evaluating how and
when to apply novel AR-directed therapeutics.
AR MUTATION
Mutation of the AR gene is not typically observed
in hormone-therapy–naïve tumors; by contrast, gainof-function AR mutations are quite common in CRPC,
and have been observed in up to 25% of recurrent tumors. These gain-of-function mutations occur most frequently in the AR ligand-binding domain and render
the receptor susceptible to an expanded set of ligands
as agonists, including both other steroid hormones (eg,
estrogen, progesterone, cortisol) and first-generation
6 Hospital Physician Board Review Manual
AR antagonists.61,62 Initial observations supporting the
existence of AR mutations were noted by clinical assessment of flutamide withdrawal syndrome,63 wherein
an antitumor response was observed upon cessation of
flutamide (AR antagonist) treatment, thus indicating
that in this subset of tumors, flutamide was serving a
pro-tumorigenic role. It was subsequently discovered
that tumors associated with flutamide withdrawal syndrome had developed a specific somatic mutation in
AR (mutation of threonine 877 to alanine), and that
this mutation altered the receptor such that flutamide
could function as an agonist that promoted AR function. Recent findings further demonstrated that mutations are selected for during first-line treatment,64,65 and
that the specific treatment regimens select for a specific
subset of AR mutations. The impact of these alterations may go beyond conferring resistance to therapy,
but may also be associated with or promote aggressive
tumor phenotypes. For example, recent assessment of
circulating tumor cells (CTCs) revealed that AR mutations were detected in the CTCs of a large fraction of
CRPCs (20 of 35 patients). Moreover, these findings
suggest that the frequency of alteration may be higher
in cells with metastatic potential.66 How to identify and
treat tumors with somatic mutations that expand and
alter AR activity remains a major clinical challenge.
AR SPLICE VARIANTS (TRUNCATED RECEPTORS)
In addition to therapy-selected AR mutations, new
findings show that castration-therapy also selects for
expression of “short forms” of the AR that largely result
from alternative splicing events. A large number of
AR splice variants have been reported, but the majority of these share loss of the sequences encoding the
ligand-binding domain of the receptor as a common
feature.67–69 Loss of the ligand-binding domain has long
been known to result in a weak but constitutively active
receptor that is refractory to both agonists and antagonists. Thus, the truncated proteins encoded by AR
splice variants are resistant to all currently approved ARdirected therapeutics. Interestingly, the splice-variant–
derived proteins appear to promote transcriptional
programs distinct from the full-length receptor, and
investigation of these gene expression programs further
support the contention that the truncated receptors
may contribute to castration resistance.70 If correct,
developing means to treat tumors expressing significant
levels of the truncated receptors may present a major
clinical difficulty. Promising new directions were initiated by development of the small molecule EPI-001,
which directly binds to the AR transactivation domain
instead of the ligand-binding domain and inhibits
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protein-protein interactions required for receptor activity. Moreover, EPI-001 suppresses association of AR
with chromatin-bound regulatory elements,71 and this
second function is thought to contribute to the agent’s
function in suppressing both long- and short-form AR
activity. Consonantly, objective cellular outcomes were
observed, wherein EPI-001 suppressed CPRC tumor cell
growth in vivo without overt host toxicity. These studies
are the first to demonstrate feasibility for in vivo suppression of AR using an agent that functions through the
AR N-terminus instead of the ligand-binding domain,
and they also provide proof-of-principle that agents can
likely be developed to treat tumors expressing receptors
lacking the ligand-binding domain.
INTRACRINE ANDROGEN SYNTHESIS
Recent evidence has shown that in response to
castration therapy, tumors develop means to induce
intracrine androgen synthesis and therefore restore
testosterone levels in the tumor microenvironment.
This knowledge resulted in a major terminology
shift in the field, wherein use of the term “androgenindependent” cancers was no longer thought to be
correct, given evidence that the tumor cells themselves had become factories of androgen production
in a castrate patient. Intracrine androgen synthesis
occurs via induction of enzymes that convert weak
adrenal androgens to testosterone, and the molecular alterations that guide this process can been quite
varied.13,14,72 Molecular modeling showed that these
events provide levels of agonist sufficient to restore
AR activity under castrate conditions.73–78 For example,
dehydroepiandrosterone derived from the adrenals
can be converted to testosterone and DHT through
the function of tumor-derived 3β-hydroxysteroid dehydrogenase (3β-HSD/ketosteroid isomerase type 1 and
type 2 [HSD3B1, HSD3B2)], type-5 17β-HSD (aldoreductase 1C3 [AKR1C3]), and steroid-5α-reductase
(SRD5A2). Moreover, HSD3B2, AKR1C3, SRD5A1,
and AKR1C2 expression is altered in CRPC, further
supporting the postulate that intracrine androgen
synthesis is a major contributor to CRPC. Modeling of
these events resulted in findings consistent with this
hypothesis, as upregulation of genes associated with
androgen synthesis from cholesterol was observed
after androgen depletion in cell-based models,79,80 and
de novo DHT synthesis has been reported in CRPCs.
Encouragingly, these findings have been rapidly translated into the clinic and resulted in development of
new therapeutic regimens that are showing clinical
benefit. As will be discussed below, the CYP17,20-lyase
inhibitor abiraterone acetate81,82 targets the intracrine
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androgen synthesis process, and use of this agent has
shown clinical benefit in patients with CRPC.
IMPACT OF AR-DEPENDENT CHROMOSOMAL
TRANSLOCATIONS
The ability of prostate cancer cells to restore AR
function after castration therapy as a means to promote
disease progression is remarkable, and is reminiscent
of oncogene-addiction exemplified in other tumor
types. In addition to the ability of AR to orchestrate
pro-proliferative and prosurvival gene expression programs in prostate cancer cells, it is now evident that in
the presence of DNA damage, AR promotes formation
of chromosomal translocations thought to induce aggressive tumor phenotypes.83 Put simply, induction of
AR-dependent gene expression is associated with chromatin looping, such that AR binding sites within the
proximal promoters and distal enhancers that control
AR target gene expression come into close proximity.
After genotoxic insult, DNA break resolution is thought
to result in AR-dependent chromosomal fusions that
can promote tumor cell phenotypes. Resulting gene
rearrangements frequently position AR-binding sites
upstream and in control of genes whose functions are
decidedly pro-tumorigenic, as is exemplified by generation of TMPRSS2:ETS gene fusions.84–90 TMPRSS2 is a
well-established AR target gene, and the TMPRSS2:ETS
gene rearrangement places ETS gene expression under
control of AR. This class of gene rearrangement occurs
in approximately 50% of all prostate cancers84,87,88,91–96
and is the most common genetic translocation in any
solid malignancy.84,87,97 Modeling of the ETS gene
fusions revealed a contribution to carcinogenesis in
vivo,84–87,98–103 and these fusions are associated with aggressive phenotypes,86,104 including increased migration
and invasive potential.85,86,89,100,105,106 Thus, genetic alterations downstream of and dependent on AR contribute
to a cascade of events that promote disease progression.
ADVANCES IN TARGETING HORMONE
THERAPY–RESISTANT DISEASE
Dramatic advances have been realized over the past
3 years with regard to treatment of metastatic CRPC,
made possible through a greater understanding of AR
signaling and the molecular basis of treatment resistance. In 2010/2011 alone, 4 different clinical trials
reported increased overall survival for new therapeutic
agents (abiraterone acetate, cabazitaxel, sipuleucel-T,
and radium-223). These new regimens are FDA-
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approved, except for radium-223, and each is likely to
change the course of treatment for patients with disseminated disease.
ABIRATERONE ACETATE
The CYP17,20-lyase inhibitor81,82 abiraterone acetate
is a pregnenolone-derived 3-pyridyl steroidal agent that
irreversibly inhibits androgen biosynthesis. Phase I/II
studies using abiraterone as a single agent resulted in
PSA declines of 50% or more in 50% to 60% of patients, and radiological response rates were observed in
both the prechemotherapy (37%) and postdocetaxel
(27%) settings.107–110 Most importantly, overall survival
in a large phase III randomized trial was significantly
longer in patients receiving abiraterone (14.8 months)
versus placebo (10.9 months).111 This benefit was observed in all subgroups, including patients with a high
pain inventory and in men aged 75 years and older.
Currently, determining how to sequence abiraterone
optimally for treatment of patients with CRPC is of
critical importance—trials are currently underway to
assess its impact in patients with asymptomatic to mildly
symptomatic prechemotherapy CRPC, in combination
with antiandrogens, and in both the pre- and postchemotherapy settings (www.clinicaltrials.gov).
CABAZITAXEL
The tubulin-binding agent cabazitaxel, approved
by the FDA in 2010, shows anticancer activity in model
systems resistant to first-generation taxanes (paclitaxel
and docetaxel). The agent showed positive results in
a phase III randomized trial that compared a cabazitaxel plus prednisone regimen with a mitoxantrone
plus prednisone regimen in patients who progressed
on or after docetaxel therapy.112 Cabazitaxel increased
median overall survival from 12.7 to 15.1 months. Currently, the agent is being evaluated as a first-line chemotherapy for patients who fail hormone therapy.12
RADIUM-223
Radium-223 is a bone-seeking, alpha-radiation–emitting radioisotope that has preferential uptake in skeletal metastases (versus normal bone).113 As opposed to
other bone-targeting radioisotopes (eg, strontium-89
and samarium-153), radium-223 has a high linear energy
transfer but a short range of action (approximately 100
µM) and induces double-strand breaks. A randomized,
placebo-controlled phase II study of patients with bone
metastases of CRPC showed an increase in progressionfree survival (26 weeks versus 8 weeks) and prolonged
survival (65 weeks versus 46 weeks),114 and the ALSYMPCA phase III trial showed improved overall survival.12 The
8 Hospital Physician Board Review Manual
agent is now on Fast Track designation by the FDA, and
may provide a benefit in the postchemotherapy setting.
SIPULEUCEL-T
Immunotherapies may offer a new approach for
treatment of advanced disease. Sipuleucel-T, an autologous activated dendritic cell therapy, was recently approved by the FDA. A clinical trial of patients who were
largely (80%) chemotherapy-naïve showed that the
agent rendered an overall survival benefit over placebo
of 25.8 versus 21.7 months.115 Current clinical reports
suggest that the agent is beneficial most frequently in
patients who are asymptomatic.
NEXT-GENERATION AR ANTAGONISTS
It is important to note that next-generation AR antagonists may function in a distinct molecular manner,
and appear to provide additional clinical benefit. The
darylthiohydantoin MDV3100 (now known as enzalutamide and approved by the FDA in September 2012)
is similar to bicalutamide in structure and binds AR
through the ligand-binding domain, but has additional
activities.116 These novel functions include the ability
to reduce nuclear accumulation of AR, and therefore
dampen chromatin association, cofactor recruitment,
and AR-dependent transcriptional activation. Interim
results of a phase I/II trial involving patients who were
either chemo-naïve or post-chemotherapy with progression of CRPC showed that the drug is well tolerated; in
addition, almost half of the patients showed at least a
50% PSA decline at week 12, with 38% of evaluable patients showing a partial reduction in tumor volume via
radiograph.117 Most recently, enzalutamide was shown
in a phase III double-blind, placebo-controlled trial of
men with CRPC to significantly prolong survival after
chemotherapy (AFFIRM trial).118 Specifically, overall
survival was increased from 13.6 to 18.4 months, and
all secondary endpoints (reduction in PSA by 50% or
more, soft tissue response rate, quality-of-life response
rate, time to PSA progression, radiographic progression-free survival, and time to the first skeletal-related
event) showed superiority of enzalutamide over placebo. Given these encouraging results, how this novel
antiandrogen might alter prostate cancer management
is an active area of investigation.
SUMMARY
Over the past decade, there has been a remarkable
expansion in our understanding of the mechanisms
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M e c h a n i s m s o f D i s e a s e P r o g r e s s i o n a n d Tr e a t m e n t R e s i s t a n c e
that drive resistance to first-line therapy for prostate
cancer and transition to the stage of castration resistance. Based on the knowledge that CRPC occurs as
a result of restored androgen signaling and AR activity, new therapeutic agents have been developed and
approved that show some efficacy at treating this late
stage of disease. Challenges remain in terms of determining how to stratify patients into the most effective
treatment options, and to determine whether complete
ablation of AR activity (if achieved) will result in cure
or development of adaptive processes that foster tumor
recurrence.
BOARD REVIEW QUESTIONS
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