Download Mechanisms Underlying the Development of Androgen

Molecular Pathways
Mechanisms Underlying the Development of Androgen-Independent
Prostate Cancer
Kenneth J. Pienta and Deborah Bradley
Background
Recent Advances
Prostate cancer continues to be the most common lethal
malignancy diagnosed in American men and the second
leading cause of male cancer mortality. The American Cancer
Society estimates that during 2005, f232,090 new cases of
prostate cancer will be diagnosed in the United States and
30,350 men will die of metastatic disease (1). Approximately 1
man in 5 will be diagnosed with prostate cancer during his
lifetime, and 1 man in 33 will die of this disease. As the
population ages, these numbers are expected to increase.
Initially, almost all metastatic prostate cancers require testosterone for growth, and the role of androgen deprivation as a
first-line therapy for metastatic prostate cancer has been
recognized for more than 60 years (2, 3). Hormone deprivation
is accomplished by surgical (orchiectomy) or medical (luteinizing hormone-releasing hormone agonists, antiandrogens)
castration. Hormonal therapy leads to remissions lasting 2 to 3
years; however, virtually all patients progress to a clinically
androgen-independent state resulting in death in f16 to 18
months (4 – 9).
Androgens are primary regulators of normal prostate as well
as prostate cancer cell growth and proliferation. During
androgen-dependent progression, prostate cancer cells depend
on the androgen receptor as the primary mediator of growth
and survival (10 – 12). When testosterone enters the cell, it is
converted by the enzyme 5a-reductase to its active metabolite,
dihydrotestosterone, a more active hormone with a 5- to 10fold higher affinity for the androgen receptor. Dihydrotestosterone binds androgen receptors in the cytoplasm, causing
phosphorylation, dimerization, and subsequent translocation
into the nucleus, thereby binding to the androgen-response
elements within the DNA, with consequent activation of genes
involved in cell growth and survival (10). During androgenindependent progression, prostate cancer cells develop a variety
of cellular pathways to survive and flourish in an androgendepleted environment. Postulated and documented mechanisms include androgen receptor (AR) gene amplification,
AR gene mutations, involvement of coregulators, ligandindependent activation of the androgen receptor, and the
involvement of tumor stem cells (Fig. 1; refs. 8, 10 – 14).
Authors’Affiliation: Michigan Urology Center, University of Michigan, Ann Arbor,
Michigan
Received 1/11/06; revised 1/26/06; accepted 1/27/06.
Grant support: University of Michigan Prostate Specialized Program of Research
Excellence, NIH grant P50CA69568.
Requests for reprints: Kenneth J. Pienta, Michigan Urology Center, University of
Michigan, 7308 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 481090946. Phone: 734-647-3421; Fax: 734-647-9480; E-mail: kpienta@ umich.edu.
F 2006 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-06-0067
www.aacrjournals.org
Hypersensitive Pathway. One way in which prostate cancer
cells circumvent the effects of androgen blockade is by
developing the ability to use very low levels of androgen for
growth (14 – 16). Hence, they do not become androgen
independent in the classic sense, but rather castration
independent. There are several proposed mechanisms that
could explain response to lower levels of androgen.
One such mechanism is increased expression of the
androgen receptor, allowing enhanced ligand binding. The
existence of this pathway is supported by studies of hormonerefractory tumors that have shown increased expression of
androgen receptor compared with androgen-dependent
tumors (14, 17 – 22). Increased production of androgen
receptor is likely secondary to gene amplification as a result
of mutation or through selective pressure of the androgendepleted environment, causing the cells with fewer androgen
receptors to die off and the clonal expansion of cells with
more androgen receptor. Chen et al. (14) have shown,
through comprehensive gene profiling of seven human
prostate cancer xenograft models, that AR gene expression
was up-regulated in the progression from androgen-dependent
to castration-independent growth. Chen et al. (14) also
showed that androgen-independent cells require 80% lower
concentrations of androgen than androgen-dependent cells
for growth.
Increased sensitivity of the androgen receptor to androgens
has been proposed as another mechanism for castration
independence (15). Using the prostate cancer cell line LNCaP,
which has a mutated androgen receptor, Gregory and coworkers have shown high level expression of the androgen
receptor, increased stability of the androgen receptor, and
enhanced nuclear localization of the androgen receptor in
recurrent prostate tumors associated with an increased sensitivity to the growth-promoting effects of dihydrotestosterone.
The concentration of dihydrotestosterone required for growth
stimulation of androgen-independent cells was 4 orders of
magnitude lower than that required for androgen-dependent
LNCaP cells (15).
A third hypersensitive mechanism proposed is increased local
production of androgens by prostate cancer cells themselves.
This most likely occurs by increased rate of conversion of
testosterone to dihydrotestosterone by increasing 5a-reductase
activity (10). Evidence in support of this mechanism includes
(a) ethnic groups with higher levels of 5a-reductase activity
have a higher rate of prostate cancer (23); (b) after androgen
ablation therapy, serum testosterone levels decrease by 95%,
but concentration of dihydrotestosterone in prostatic tissue is
reduced by only 60% (24); and (c) genes involved in steroid
biosynthesis have been found to be overexpressed in recurrent
human prostate tumors (22).
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Molecular Pathways
Fig. 1. Mechanisms of androgen independence. 1, amplification. Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of
the androgen receptor (AR ; usually by gene amplification), increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to
dihydrotestosterone by 5a-reductase (5aR). 2, promiscuous binding. Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid
molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor. 3, outlaw pathway. Nonsteroid molecules activate the
androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms [e.g., epidermal growth factor
(EGF)]. 4, bypass pathway. Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation
of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when
they are exposed to lack of testosterone. 5, coregulators. Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between
the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative
mechanisms of activation. 6, stem cell regeneration. Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the
tumor cell population despite therapy.
Promiscuous Receptor. Although the wild-type androgen
receptor is activated only by testosterone and dihydrotestosterone, the specificity of the androgen receptor has been shown to
be broadened by mutations. The majority of mutations
discovered leading to binding promiscuity are clustered in the
ligand-binding domains (25, 26). These mutations allow the
androgen receptor to be activated by nonandrogenic steroid
molecules normally present in the circulation as well as
antiandrogens (10– 12, 14, 27– 31). Such mutations have been
shown to be more frequent in androgen-independent prostate
cancer cells and form the basis of antiandrogen withdrawal
syndromes in which f10% to 30% of patients treated with
long-term antiandrogens will show disease regression with drug
withdrawal (32– 35).
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Outlaw Pathway. It has also been determined that activation of androgen receptor can be accomplished by liganddependent binding of nonsteroid molecules or activation of
downstream signaling of the androgen receptor by ligandindependent mechanisms. Growth and proliferation of tumor
cells is therefore no longer under androgen control, although
the androgen receptor machinery remains active. This type of
activation has been coined outlaw activation (10 – 13).
Deregulated growth factors, including insulin-like growth
factor, keratinocyte growth factor, and epidermal growth
factor, and cytokines, including IL-6, have been shown to
directly phosphorylate and activate the androgen receptor (36,
37). In addition, it has been shown that androgen receptor–
dependent genes can be activated by deregulation of signal
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Development of Androgen-Independent Prostate Cancer
transduction pathways (38, 39). For example, overexpression of
the receptor tyrosine kinase HER-2/neu has been shown to
activate androgen receptor –dependent genes in the absence of a
ligand (38, 39).
The activation of outlaw pathways spotlights the potential
importance of tumor-microenvironment interactions in the
development of castration-independent growth (40, 41). Paget
(42) recognized that a ‘‘fertile soil’’ was necessary for the
successful growth of cancer metastases. For example, many
factors contribute to both androgen-dependent and independent growth of prostate cancer in the bone (41). The interaction
of prostate cancer cells with bone stromal cells, osteoblasts, and
osteoclasts, as well as the remodeling of bone extracellular
matrix, results in the release and deregulation of multiple
growth factors that the prostate cancer cells can use to become
androgen independent.
Coactivators and Corepressors. A large number of coactivators
and corepressors involved in the regulation of androgen
receptor–driven transcription have been identified (43). They
function as signaling intermediaries between the androgen
receptor and general transcriptional machinery. Alterations in
the balance between coactivators and corepressors have been
shown to influence androgen receptor activation, although the
precise mechanisms remain unknown (10, 44–47). An increase
in coactivator levels has been shown in androgen-independent
disease (44, 48–51). Coactivator proteins have been shown to
enhance the activity of the androgen receptor to alternative
ligands, sensitize the receptor to lower levels of native and
Fig. 2. Targeting critical pathways and the tumor microenvironment of androgen-independent prostate cancer. Targeted therapies are being developed that block outlaw
signal transduction pathways to prevent ligand-independent phosphorylation of the androgen receptor, including agents that inhibit growth factor receptors directly
(e.g., epidermal growth factor receptor by gefitinib) or indirectly through inhibition of downstream signal transduction (e.g., inhibition of ras by reolysin or bRaf by
BAY43-9006). The bypass pathway is being targeted by chemotherapeutic agents such as docetaxel as well as specific inhibitors of Bcl-2 (gossypol and the antisense
molecule G3139) as well as clusterin (the antisense molecule OGX-011). Geldanamycin is an antibiotic that destabilizes heat shock protein 90 and targets the hypoxia pathway
as well as the androgen receptor signaling pathway. The tumor microenvironment is now actively targeted by agents which bind bone hydroxyapatite and inhibit osteoclast
function, including zoledronate and the radioisotopes samarium and strontium. The signal transduction of supporting cells is being targeted by vascular endothelial growth
factor antibodies (endothelial cells) and endothelin-1 (ET-1) receptor antagonists (osteoblasts). Stimulation of the immune system to recognize prostate cancer cells as foreign
is being pursued through multiple vaccine strategies (e.g., APC8015, GVAX, and TRICOM-vaccinia). GF, growth factor; VEGF, vascular endothelial growth factor receptor;
PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; ET-R, endothelin receptor; RTK, receptor tyrosine kinase; mTOR, mammalian target
of rapamycin.
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Molecular Pathways
nonnative ligands, and to allow ligand-independent activation
(44, 52).
Bypass Pathway. Alternatively, the androgen receptor pathway can be bypassed completely and prostate cancer cells
develop the ability to survive independent of ligand-mediated
or non-ligand-mediated androgen receptor activation. The best
known bypass mechanism involves modulation of apoptosis.
In androgen-dependent prostate cancer cells, androgen receptor
activation stimulates cell proliferation and depletion of androgen leads to apoptosis of these cells. Androgen-independent
prostate cancer cells have been shown to frequently up-regulate
antiapoptotic molecules (53 – 56). Inactivation of the tumorsuppressor gene phosphatase and tensin homologue with
subsequent activation of Akt is one way in which androgenindependent prostate cancer cells escape apoptosis in an
androgen-depleted environment (12). Another postulated
bypass mechanism is the neuroendocrine differentiation of
prostate cancer cells (12). Neuroendocrines cells have a low
rate of proliferation and are more prevalent in androgenrefractory prostate cancer (12). They also secrete neuropeptides,
such as serotonin and bombesin, which can increase the
proliferation of neighboring cancer cells, allowing progression
in a low-androgen environment (12).
Prostate Cancer Stem Cells. In contrast to the stochastic
model of tumorigenesis, in which every cell within the tumor is
potentially tumor-initiating, the stem cell model of cancer, or
the hierarchical model, postulates that only a rare subset of cells
are tumorigenic (54). A population of cells comprising 0.1% of
prostate tumors, which are CD44+/a2h1/CD133+ and do not
express androgen receptors, has been identified and is thought
to be prostate cancer stem or progenitor cells (57). Another
potential mechanism for survival in the androgen-depleted
environment is the presence of prostate cancer stem cells that
continually resupply the tumor cell population, despite
therapy. Although these cells remain a small percentage of the
actual percentage of the tumor, they are not affected by
androgen-depletion therapy. These stem cells differentiate into
androgen-dependent and independent cells, resulting in the
heterogeneous androgen receptor phenotype that is observed
in androgen-independent patients (8).
Therapeutic Implications
Novel Strategies to Target Hormone Refractory Prostate
Cancer. Ultimately, understanding the mechanisms is not
enough. Understanding the pathways to what we now know as
castration-resistant prostate cancer offers specific therapeutic
opportunities based on these mechanisms (40, 41, 58). As in
many cancers, novel therapies are being approached with two
different strategies. The first is the identification of critical
pathways and targets. The second is the development of
multitargeted approaches that are directed not only at the
cancer cell but also at the surrounding microenvironment of
the tumor (Fig. 2).
Critical Pathways. Bypass pathways that promote cell
survival are being targeted with a variety of strategies.
Targeting the Bcl-2 molecule-microtubule complex with the
agent docetaxel has led to the first shown survival benefit for
patients with androgen-independent prostate cancer (58). In
a trial involving 1,006 men with hormone refractory prostate
cancer, Tannock et al. (59) reported in 2004 that 75 mg/m2
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of docetaxel given every 3 weeks plus daily prednisone led
to a median survival rate of 18.9 months, compared with
a survival rate of 16.4 months in patients who received 12
mg/m2 of mitoxantrone given every 3 weeks plus daily
prednisone (P = 0.009). As compared with the mitoxantrone
group, those given docetaxel every 3 weeks had a hazard ratio
for death of 0.76 (95% confidence interval, 0.62-0.94; P =
0.009). The every-3-week schedule of docetaxel showed an
advantage in median survival when compared with mitoxantrone (18.9 versus 16.4 months; P = 0.009). Docetaxel every
3 weeks plus prednisone therapy also resulted in improvement in pain, a decrease in prostate-specific antigen, and
improved quality of life compared with mitoxantrone plus
prednisone.
G3139 (oblimersen sodium) is an antisense oligonucleotide
directed against Bcl-2 mRNA that seems to have clinical activity
in conjunction with docetaxel (60). Several trials are under
way with the polyphenol gossypol and its derivatives inhibit
Bcl-2, Bcl-xL, and cyclin D1 (61). An antisense molecule to
clusterin, a prosurvival gene that is up-regulated in androgenindependent prostate cancer, is currently in clinical trials (62).
1,25-Dihydroxycholecalciferol (calcitriol) potentiates the activity of chemotherapeutic agents by causing G0-G1 arrest and
inducing apoptosis. The combination of calcitriol and docetaxel
seems to have increased antitumor activity as compared with
docetaxel alone and is the subject of ongoing investigation (63).
Although new chemotherapeutic drugs such as satraplatin
and the epothilones are in clinical trials in advanced prostate
cancer, the most exciting progress is being made in targeting
outlaw signal transduction pathways that are deregulated in
prostate cancer (58, 64 – 66). Outlaw pathways often rely on the
activation of the tyrosine kinase growth factor receptors.
Antibodies and small molecules that target growth factor
receptors on prostate cancer cells include those directed against
epidermal growth factor receptor (gefitinib, cetuximab, trastuzumab, lapatinib, and erlotinib) and platelet-derived growth
factor receptors (imantinib and leflunomide; refs. 41, 67).
Other tyrosine receptor pathway inhibitors include BAY439006, reolysin, LErafAON, and GEM 231. Many of these
pathways can also be targeted in the supporting cells of the
tumor. The now classic example of this is the use of agents that
target the vascular endothelial growth factor pathway to
interrupt the blood supply to the tumor cells (68). A phase
III trial of bevacizumab (Avastin) and docetaxel is being done
by the Eastern Cooperative Oncology Group. Another such
agent is atrasentan, which targets the endothelin-1 axis in
osteoblasts (69). This agent, in combination with docetaxel, is
the subject of a phase III trial by the SouthWest Oncology
Group. As the role of the androgen receptor in androgenresistant disease has been recognized, it has become a focus of
therapeutic development.
In focusing on targeting the hypersensitive pathway, one
approach has been to try to lower androgen receptor protein
levels. Ansamycin antibiotics, such as 17-allylamino-17-demethoxygeldanamycin, have been shown in preclinical models to
induce degradation of steroid receptors, including the
androgen receptor, by inhibiting heat shock protein 90, a
chaperone required for the folding of these proteins, and are
currently in phase I trials (70 – 73). In preclinical studies, Eder
et al. (74) were able to inhibit androgen receptor expression
in LNCaP tumor cells using antisense androgen receptor
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oligodeoxynucleotides resulting in decreased growth, decreased
production of prostate-specific antigen, and increased apoptosis. Further advances are also being made to reduce testosterone
beyond the currently known second-line and third-line hormonal agents; it was recognized that much less ligand is needed
for androgen receptor activation in hormone-refractory prostate
cancer cells (75).
A large number of coactivators and corepressors involved in
the regulation of androgen receptor – driven transcription have
been identified (43). Because it is known that ligand-dependent
and ligand-independent androgen receptor transcriptional
activity is dependent on coactivator recruitment, modification
of these coregulators or their binding targets may be important
therapeutically. Peptide antagonists that target specific nuclear
receptor coactivator binding surfaces have been developed in
the preclinical setting and have been shown to inhibit
androgen receptor transcriptional activity by disrupting androgen receptor-coactivator interactions (76).
The signal transduction pathways associated with tumor
hypoxia has been the subject of intense scrutiny because they
involve the outlaw, bypass, and cofactor pathways (77). CCI779 and RAD001 target the mammalian target of rapamycin
and upstream regulator of hypoxia-inducible factor 1a
(78 – 80). Hypoxia-inducible factor 1a is also regulated through
its binding to heat shock protein 90, which prevents its
degradation by the proteosome complex (80). Heat shock
protein 90 also stabilizes multiple other enzymes that are part
of tyrosine kinase signaling cascades, as well as other proteins,
such as steroid receptors including the androgen receptor (81).
The geldanamycin derivative 17-(allylamino)-17-demethoxygeldanamycin is an antibiotic that inhibits heat shock protein
90 function, leading to proteosome degradation of these
multiple signaling targets (77 – 81).
Multitargeted Attack of the Cancer Cell and the Tumor
Microenvironment. While other molecular targets, including
the mitotic kinesins, histone deacetylases, the small-molecule
inhibitor suberoylanilide hydroxamic acid, and cyclic GMP
phosphodiesterases, are being pursued, the combination of
multiple agents that simultaneously attack the tumor and its
microenvironment are being developed as well as already being
used in the clinic (41, 82, 83). Prostate cancer cells in the bone
interact with the extracellular matrix, stromal cells, osteoblasts,
osteoclasts, and endothelial cells to coordinate a sophisticated
series of interactions to promote tumor cell survival and
proliferation (41, 84). The Food and Drug Administration –
approved bisphosphonate zoledronic acid binds to the
hydroxyapatite of damaged bone and inhibits osteoclast
function, leading to a decrease in skeletal related events, such
as fractures, in patients with hormone refractory prostate cancer
(85, 86). Similarly, the radioisotopes samarium and strontium
have been Food and Drug Administration approved for
patients with bone metastases because they, too, bind to
hydroxyapatite and deliver radiation to the entire tumor
microenvironment, damaging not only the cancer cells but
all of the supporting cells of the microenvironment (87, 88).
The benefits of these agents in decreasing the morbidity of
metastatic prostate cancer have been clearly delineated. Agents
that deliver radiation to all prostate cancer cells, whether they
reside in bone or soft tissue sites, are in clinical trials. Prostatespecific membrane antigen is a transmembrane glycoprotein
that is highly expressed by prostate cancers and trials using
antibodies to prostate-specific membrane antigen conjugated
to multiple different radiopharmaceuticals and chemotherapy
agents are under way (89).
All of these approaches can be complemented by strategies
that exploit the immune system. Several vaccine strategies that
either increase the antigenicity of prostate cancer cells or
sensitize dendritic cells to the presence of prostate cancer cells
are in clinical trials. These include APC8015 (Provenge), an
investigational therapeutic vaccine that uses autologous
antigen-presenting cells loaded with a recombinant fusion
protein of prostatic acid phosphatase linked to a molecule
that specifically targets a receptor expressed on the surface of
human antigen-presenting cells, GVAX, an autologous tumor
vaccine in which cells from the patient’s tumor are transduced
in vitro with an engineered adenovirus containing the GM-CSF
gene and poxvirus-TRICOM combinations (90 – 92).
Conclusion
The treatment of hormone-refractory prostate cancer is
evolving rapidly. The definition of the multiple mechanisms
by which prostate cancer cells can become resistant to
castration has led to the identification of several new leads
and pathways that are being quickly exploited. Combining this
knowledge with a multifaceted attack on the tumor microenvironment that includes therapy involving endothelial cells,
osteoblasts, osteoclasts, tumor stroma, and immune modulation should lead to a rapid increase in survival in patients with
hormone-refractory prostate cancer in the near future.
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Mechanisms Underlying the Development of
Androgen-Independent Prostate Cancer
Kenneth J. Pienta and Deborah Bradley
Clin Cancer Res 2006;12:1665-1671.
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