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Drug Discovery Today Volume 00, Number 00 August 2014 REVIEWS

Strategies for targeting the androgenreceptor axis in prostate cancer

Brett S. Carver

Department of Surgery, Division of Urology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Androgen receptor (AR) signaling plays a critical role in prostate cancer cell proliferation, survival, and

differentiation. Therapeutic strategies targeting the androgen receptor have been developed for the

treatment of metastatic hormone-nave prostate cancer; however, despite effective targeting recent

studies have demonstrated that during progression to a castrate-resistant phenotype there is restoration

of AR target gene expression. On the basis of this observation, second-generation therapeutics have been

developed to target AR in the castrate-resistant setting resulting in a survival benefit. In this review we

will discuss the mechanisms promoting AR signaling and the development of second-generation

therapeutics targeting AR in castrate-resistant prostate cancer.IntroductionThe androgen receptor (AR) gene, located on chromosome Xq11

12, encodes for a 110 kDa nuclear receptor protein that activates or

represses the transcription of target genes. These androgen-regu-

lated genes modulate cell growth, differentiation and homeostasis

of androgen-dependent cells. AR signaling is crucial for the devel-

opment and maintenance of male reproductive organs including

the prostate gland. The dependence of prostate cancer cells on

androgen signaling was first demonstrated by Huggins and Hodges

who observed that bilateral orchiectomy resulted in regression of

disease in patients with metastatic prostate cancer [1]. Since that

time, androgen-deprivation therapy has been the treatment of

choice for metastatic and locally advanced prostate cancer. How-

ever, despite androgen-deprivation therapy, the majority of meta-

static prostate cancers progress to a castrate-resistant phenotype

[2,3]. Although a minority of castrate-resistant prostate cancers

bypass the requirement for AR signaling (neuroendocrine and

small-cell differentiation lacking AR expression), the vast majority

remain dependent on the androgen pathway. In this review we

will discuss the molecular mechanisms of AR signaling in castrate-

resistant disease and therapies directed at further inhibiting AR

function in the castrate-resistant setting.Please cite this article in press as: Carver, B.S. Strategies for targeting the androgen rej.drudis.2014.07.008

E-mail address: carverb@mskcc.org.

1359-6446/06/$ - see front matter 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.Castrate-resistant prostate cancer maintains afunctional AR axisProgression of metastatic prostate cancer following androgen

deprivation (castrate-resistant disease) was previously referred to

as hormone refractory prostate cancer. However, it has long been

observed clinically that this disease state is in fact still dependent

on androgen signaling. Prostate-specific antigen (PSA), an AR-

regulated gene and marker for prostate cancer disease activity as

measured by serum levels, declines following androgen-depriva-

tion therapy and a subsequent rise in serum PSA levels is often the

hallmark for the emergence of castrate-resistant disease. This

increase in serum PSA levels clearly indicates reactivation of AR

target gene activity. Additionally, after the development of cas-

trate-resistant disease, the administration of first-generation AR

antagonists, such as flutamide or bicalutamide, has been demon-

strated to elicit a therapeutic response associated with reduction in

serum PSA levels [4,5]. Thus, directly inhibiting AR in the setting of

castrate-resistant disease is associated with serum PSA responses in

the majority of patients. Lastly, patients demonstrating progres-

sion of castrate-resistant disease following treatment with fluta-

mide or bicalutamide, once again defined by increases in serum

PSA levels, were observed to have declining serum PSA levels

following antiandrogen withdrawal, indicating that the antian-

drogens began working as agonists toward AR [6,7]. Collectively,

these clinical observations led to the appreciation that castrate-

resistant disease is still dependent on AR signaling.ceptor axis in prostate cancer, Drug Discov Today (2014), http://dx.doi.org/10.1016/

07.008 www.drugdiscoverytoday.com 1

http://dx.doi.org/10.1016/j.drudis.2014.07.008http://dx.doi.org/10.1016/j.drudis.2014.07.008mailto:[2_TD$DIFF]carverb@mskcc.orghttp://dx.doi.org/10.1016/j.drudis.2014.07.008

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REVIEWS Drug Discovery Today Volume 00, Number 00 August 2014

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olecular alterations of AR in castrate-resistantrostate cancereveral molecular mechanisms have been implicated to promote

eactivation of AR in the castrate environment. Initial studies

cused directly on molecular analyses of AR in the castrate-resis-

ant setting. Investigators sequencing AR in cell lines and meta-

tatic prostate cancer specimens have identified several mutations

hat allow other steroids, such as corticosteroids, and antiandro-

ens to act as agonists. These mutations are detected in approxi-

ately 10% of castrate-resistant prostate cancers, frequently

bserved following antiandrogen therapy, although the actual

cidence could be higher [8,9]. The majority of mutations occurs

the ligand-binding domain of the AR, resulting in structural

hanges in the AR protein altering the specificity of ligand bind-

g. Thus, the mutated AR can be activated by other steroid

ormones such as progesterone or convert known AR antagonists,

uch as flutamide, to agonist activity.

Other mechanisms resulting in activation of AR include ampli-

cation of AR, upregulation of AR expression, expression of AR

ranscript variants lacking the ligand-binding domain, modula-

ion of AR co-factors and activation of kinase pathways promoting

R function. Figure 1 summarizes the potential mechanisms of AR

ctivation in castrate-resistant disease and rationale for the devel-

pment of therapeutics targeting these mechanisms.

mplification and overexpression of AR in castrate-esistant prostate cancerverexpression of AR is a frequent event in prostate cancer.

ompared to hormone-naive organ-confined prostate cancer, cas-

rate-resistant prostate cancer is enriched for AR amplification and

creased AR gene expression. Although AR amplification has not

een observed in primary prostate cancer, approximately 20% of

astrate-resistant metastases will demonstrate AR amplification

012]. Furthermore, mRNA upregulation is observed in approxi-

ately 60% of castrate-resistant prostate cancers [12,13]. Studies

ave demonstrated that exogenous overexpression of AR is suffi-

ient to induce castrate-resistant disease in preclinical models [14].

triguingly, overexpression of AR also resulted in reduced efficacy

f the antiandrogen bicalutamide, converting this AR antagonist

o a weak agonist in cell lines and xenograft models [14]. In

onjunction with the overexpression of AR, it has been observed

hat there is an associated increase in the expression of transcript

ariants of AR lacking the ligand-binding domain while maintain-

g functional activity even in the absence of androgens.

ndrogen production in castrate-resistant prostateancerndrogen deprivation therapy does not completely eliminate cir-

ulating serum androgens. Serum testosterone levels are reduced to

mean of 15 ng/ml from a normal range of greater than 200 ng/ml,

hereas serum levels of adrenal androgens such as androsteindione

nd dehydroepiandrosterone (DHEA) are unaffected following an-

rogen-deprivation therapy [15]. Studies have demonstrated that

drenal androgens and downstream metabolites are capable of

inding to and activating the AR in a castrate setting [16,17].

lthough serum testosterone levels significantly decrease following

ndrogen-deprivation therapy, the intraprostatic concentration of

ndrogens is reduced much less dramatically [18]. Although thisPlease cite this article in press as: Carver, B.S. Strategies for targeting the androgen j.drudis.2014.07.008

www.drugdiscoverytoday.comlevel of reduction is sufficient to induce cellular response in hor-

mone-naive prostate cancer, molecular alterations evolve that result

in an increased sensitivity of AR to low levels of ligands in the

castrate-resistant setting.

In addition to low-level production of testosterone by the testes

following androgen-deprivation therapy, the adrenal glands also

serve as a source of circulating androgens promoting castrate-

resistant disease. Recent data are also emerging to support the fact

that intratumoral production of androgens could also play an

important part. Expression profiling studies comparing castrate-

resistant prostate cancer with primary tumors found that enzymes

involved in androgen synthesis, such as cytochrome P450

(CYP)17, are upregulated in castrate-resistant disease [13,19,20].

These enzymes play a crucial part in the conversion of cholesterol

and pregnenolone to androgens (DHEA). Furthermore, using mass

spectrometry to measure intratumoral androgens directly, it has

been shown that castrate-resistant metastatic prostate cancers

have higher levels of testosterone compared with primary tumors

in hormone-naive patients [21]. These data suggest that adrenal

and intratumoral production of androgens might allow prostate

cancers to progress despite low serum testosterone levels associat-

ed with androgen-deprivation therapy. This is especially realized

in the setting of AR mutation or overexpression, where the AR is

sensitive to low levels of ligand.

Targeting the AR in castrate-resistant prostate cancerOn the basis of the knowledge that castrate-resistant prostate cancer

is still dependent on AR and the identification of molecular altera-

tions leading to AR activity despite low levels of androgen, several

novel therapies have been developed for patients with castrate-

resistant disease. At the initial progression to castrate-resistant pros-

tate cancer, an antiandrogen such as flutamide or bicalutamide is

typically combined with continued androgen-deprivation therapy

and, in some cases, this can result in stabilization of disease [4,5].

However, in the majority of patients, the time to disease progression

is usually short. These antiandrogens bind directly to the ligand-

binding domain and out-compete low levels of androgens for bind-

ing. However, because bicalutamide and flutamide allow AR nuclear

translocation and DNA binding, these antiandrogens have been

observed Q4to convert to AR agonists as demonstrated by a clinical rise

in serum PSA levels followed by a paradoxical decline upon antian-

drogen withdrawal [6,7]. Several second-generation AR antagonists

are currently in various stages of early clinical development.

MDV-3100 (enzalutamide), a novel second-generation antian-

drogen, was rationally designed using the crystal structure of the

AR and cell-based screening [14]. Because biclutamide is converted

to an agonist in LNCaP cells that overexpress AR, candidate

compounds were screened for their ability to inhibit cell growth

and PSA production. MDV-3100 binds directly to AR in the ligand-

binding domain, inhibiting the ability of AR to translocate effi-

ciently to the nucleus and bind to DNA [14]. These properties

lessen the probability of agonist conversion for MDV-3100 that

has previously been observed with earlier antiandrogens [14,22].

Furthermore, in preclinical studies MDV-3100 has demonstrated

efficacy in the setting of AR overexpression and known mutations.

A Phase III trial of MDV-3100 in patients with castrate-

resistant metastatic prostate cancer who have progressed following

chemotherapy has demonstrated a significant improvement inreceptor axis in prostate cancer, Drug Discov Today (2014), http://dx.doi.org/10.1016/

http://dx.doi.org/10.1016/j.drudis.2014.07.008http://dx.doi.org/10.1016/j.drudis.2014.07.008

Drug Discovery Today Volume 00, Number 00 August 2014 REVIEWS

DRUDIS 1465 15

AR amplificationoverexpression

AR mutation

AR variants

Transcription of AR target genes

AndrogensCYP17

Androgens

Adrenal

Androgenprecursors

AndrogenprecursorsAR

AR

AR

AR

AR

AR

Mut AR WT AR

Drug Discovery Today

FIGURE 1

MolecularQ5 mechanism of androgen receptor (AR) signaling in castrate-resistant prostate cancer. In the castrate-resistant environment AR activity can be restoredthrough: (i) the production of adrenal or intratumoral androgens; (ii) the activation of AR in a ligand-independent fashion through receptor tyrosine kinase

regulation; (iii) mutation of AR leading to alternative steroid binding or antiandrogen switch; (iv) amplification or overexpression of AR with increased sensitivity to

low levels of androgen or co-factor imbalance; (v) expression of AR transcript variants lacking the ligand-binding domain. Abbreviations: CYP, cytochrome P450;Mut, mutant; WT, wild type.

ReviewsPOSTSCREEN

median survival of approximately 4.8 months compared with

placebo [23]. Interestingly, the majority of patients who pro-

gressed following treatment with MDV-3100 demonstrated rising

PSA levels and reactivation of AR target gene expression. A recent

study from Balbas and colleagues identified, through preclinical

modeling, a mutation in AR that converts MDV-3100 from an

antagonist to an agonist [24]. This finding is currently being

evaluated in patients from the Phase III study to validate if this

mutation indeed is a mechanism of resistance in patients who

have progressed following MDV-3100.

Targeting androgen production in castrate-resistantprostate cancerIn addition to targeting the AR directly, therapies have also been

developed to inhibit the production of circulating androgens

further. Treatment with ketoconazole, a nonspecific CYP inhibitor

that targets numerous enzymes in the steroid synthesis pathway,

results in significant serum PSA reductions in 2550% of patients

with castrate-resistant prostate cancer [25]. The mechanism of

action is thought to be primarily through inhibiting production

of adrenal androgens, because patients with higher baseline adre-

nal androgen levels were found to have improved response rates

and prolonged survival following treatment with ketoconazole

[26]. Despite the improved therapeutic efficacy, nonspecific

inhibitors of CYP and steroidogenic enzymes suppress cortisol

production, and have significant constitutional side effects, limit-

ing quality of life.Please cite this article in press as: Carver, B.S. Strategies for targeting the androgen rej.drudis.2014.07.008Abiraterone (Zytiga1), a selective irreversible inhibitor of

CYP17, targets adrenal and intratumoral androgen production

without affecting cortisol production [27]. In preclinical mod-

els, abiraterone resulted in reduction of serum testosterone to

castrate levels in intact mice without affecting serum cortisol

levels, whereas ketoconazole suppressed cortical levels more

than testosterone [27]. In combination with androgen-depriva-

tion therapy, abiraterone results in a substantial decrease in the

serum levels of testosterone and adrenal androgens. Phase I/II

clinical trials in patients with castrate-resistant prostate cancer

demonstrate significant activity with PSA responses exceeding

60% in chemotherapy-naive patients and a Phase III trial of

abiraterone in patients previously treated with chemotherapy,

demonstrating a significant improvement in overall survival

[28]. Similar to the Phase III trial of MDV-3100, the majority

of patients with progression following abiraterone experienced

rising serum PSA levels and mechanisms of resistance are cur-

rently being evaluated. Similar to abiaterone, TAK-700 (orter-

onel) is a highly selective 17,20-lyase inhibitor demonstrated to

block the peripheral (adrenal, intratumoral) production of

androgens [29]. However, a Phase III trial of TAK-700 in men

with castrate-resistant prostate cancer who failed prior doce-

taxel-based chemotherapy failed to reach an endpoint of im-

proved overall survival.

Additionally, several clinical trials are currently being per-

formed in the neoadjuvant and metastatic setting to evaluate

whether complete AR pathway inhibition with abirateroneceptor axis in prostate cancer, Drug Discov Today (2014), http://dx.doi.org/10.1016/

www.drugdiscoverytoday.com 3

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ombined with ARN509, an antiandrogen similar to MDV-3100,

esults in an improved response [30].

merging approaches to targeting AR in prostateancer and concluding remarksR transcript variant domains have been shown to be upregu-

ted in castrate-resistant prostate cancer, have the capability to

egulate AR target gene activity and could promote a castrate-

esistant phenotype in the absence of ligands [31]. Because these

R variants lack the ligand-binding domain, by definition they

re resistant to inhibitors of AR acting through the ligand-

inding domain, although some controversy exists as to wheth-

r the activity of these variants requires partnering with a full

ngth AR [32]. On the basis of these AR variants and the

gonism switch that can occur with ligand-binding AR inhibi-

ors several groups have developed alternative AR inhibitors

argeting the N-terminal domain of AR as well as co-regulators

odulating AR activity. EPI-001 is an N-terminal AR inhibitor

ith promising preclinical development results, demonstrating

herapeutic efficacy in castrate-resistant prostate cancer xeno-

rafts [33].Please cite this article in press as: Carver, B.S. Strategies for targeting the androgen j.drudis.2014.07.008

www.drugdiscoverytoday.comRecently, PELP1 was identified as a crucial co-regulatory partner

of the AR complex, and disruption of this interaction leads to

reduced AR target gene activity and nuclear localization of AR [34].

Using peptidomimetic strategies several compounds have been

developed to target and inhibit the interaction of PELP1 and AR

leading to reduced AR activity. These compounds are currently in

preclinical development.

Over recent years an increasing appreciation of the role of AR in

castrate-resistant disease has led to the development of new ther-

apeutic strategies targeting the AR axis. Given that multiple mech-

anisms are responsible for AR activation in castrate-resistant

prostate cancer, the ability to define pathway alterations regulat-

ing AR in individual patients with prostate cancer is crucial to

determine which therapeutic agents or combination thereof will

provide maximal therapeutic benefit. Furthermore, based on the

progression patterns of patients following treatment with MDV-

3100 or abiraterone, further optimization of AR-targeted therapies

is also warranted.

Conflict of interestThe author has no conflicts of interest to declare.eferences1 Huggins, C. and Hodges, C.V. (1941) Studies on prostate cancer. The effect of

castration, of estrogen, and of androgen injection on serum phosphatases in

metastatic carcinoma of the prostate. Cancer Res. 1, 293297

2 Smaletz, O. and Scher, H.I. (2002) Outcome predictions for patients with metastatic

prostate cancer. Semin. Urol. Oncol. 20, 155163

3 Tannock, I.F. et al. (2004) Docetaxel plus prednisone or mitoxantrone plus

prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 15021512

4 Scher, H.I. et al. (1997) Biclutamide for advanced prostate cancer: the natural versus

treated history of disease. J. Clin. Oncol. 15, 29282938

5 Fossa, S.D. et al. (2001) Flutamide versus predisone in patients with prostate cancer

symptomatically progressing after androgen-ablative therapy: a phase III study of

the European organization for research and treatment of cancer genitourinary

group. J. Clin. Oncol. 19, 6271

6 Kelly, W.K. and Scher, H.I. (1993) Prostate specific antigen decline after

antiandrogen withdrawal: the flutamide withdrawal syndrome. J. Urol. 149,

607609

7 Culig, Z. et al. (1999) Switch from antagonist to agonist of the androgen receptor

biclutamide is associated with prostate tumour progression in a new model system.

Br. J. Cancer 81, 242251

8 Taplin, M.E. et al. (2003) Androgen receptor mutations in androgen-independent

prostate cancer: Cancer and Leukemia Group B Study 9663. J. Clin. Oncol. 21,

26732678

9 Fenton, M.A. et al. (1997) Functional characterization of mutant androgen

receptors from androgen-independent prostate cancer. Clin. Cancer Res. 3,

13831388

0 Bubendorf, L. et al. (1999) Survey of gene amplifications during prostate cancer

progression by high-throughout fluorescence in situ hybridization on tissue

microarrays. Cancer Res. 59, 803806

1 Edwards, J. et al. (2003) Androgen receptor gene amplification and protein

expression in hormone refractory prostate cancer. Br. J. Cancer 89, 552556

2 Taylor, B.S. et al. (2010) Integrative genomic profiling of human prostate cancer.

Cancer Cell 18, 1122

3 Holzbeierlein, J. et al. (2004) Gene expression analysis of human prostate carcinoma

during hormonal therapy identified androgen-responsive genes and mechanisms of

therapy resistance. Am. J. Pathol. 164, 217227

4 Tran, C. et al. (2009) Development of a second-generation antiandrogen for

treatment of advanced prostate cancer. Science 324, 787790

5 Gellar, J. (1985) Rationale for blockade of adrenal as well as testicular androgens in

the treatment of advanced prostate cancer. Semin. Oncol. 12, 283516 Mizokami, A. et al. (2004) The adrenal androgen androstenediol is present in

prostate cancer tissue after androgen deprivation therapy and activates mutated

androgne receptor. Cancer Res. 64, 765771

17 Zhao, X.Y. et al. (2000) Glucocorticoids can promote androgen-independent

growth of prostate cancer cells through a mutated androgen receptor. Nat. Med. 6,

7376

18 Mostaghel, E.A. et al. (2007) Intraprostatic androgens and androgen-regulated gene

expression persist after testosterone suppression: therapeutic implications for

castration-resistant prostate cancer. Cancer Res. 67, 50335041

19 Stanbrough, M. et al. (2006) Increased expression of genes converting adrenal

androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66,

28152825

20 Fung, K.M. et al. (2006) Increased expression of type 2,3-alpha-hydroxysteroid

dehydrogenase/type 5,17 beta-hydroxysteroid dehydrogenase (AKR1C3) and its

relationship with androgen receptor in prostatic adenocarcinoma. Endocr. Relat.

Cancer 13, 169180

21 Montogmery, R.B. et al. (2008) Maintenance of intratumoral androgens in

metastatic prostate cancer: a mechanism for castrate-resistant tumor growth. Cancer

Res. 68, 44474454

22 Scher, H.I. et al. (2010) Antitumour activity of MDV3100 in castration-resistant

prostate cancer: a phase 1-2 study. Lancet 375, 14371446

23 Scher, H.I. et al. (2012) Increased survival with enzalutamide in prostate cancer after

chemotherapy. N. Engl. J. Med. 367, 11871197

24 Balbas, M.D. et al. (2013) Overcoming mutation-based resistance to antiandrogens

with rational drug design. Elife 2, e00499

25 Small, E.J. et al. (2004) Anti-androgen withdrawal alone or in combination with

ketoconazole in androgen-independent prostate cancer patients: a phase III trial

(CALGB 9583). J. Clin. Oncol. 22, 10251033

26 Ryan, C.J. et al. (2007) Adrenal androgen levels as predictors of outcome in prostate

cancer patients treated with ketoconazole plus antiandrogen withdrawal: results

from a cancer and leukemia group B study. Clin. Cancer Res. 13, 20302037

27 Barrie, S.E. et al. (1994) Pharmacology of novel steroidal inhibitors of cytochrome

P450(17) alpha (17 alpha-hydroxylase/C1720 lyase). J. Steroid Biochem. Mol. Biol.

50, 267273

28 de Bono, J.S. et al. (2011) Abiraterone and increased survival in metastatic prostate

cancer. N. Engl. J. Med. 364, 19952005

29 Kaku, T. et al. (2011) Discovery of orteronel (TAK-700), a naphthylmethylimidazole

derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the

treatment of prostate cancer. Bioorg. Med. Chem. 19, 63836399receptor axis in prostate cancer, Drug Discov Today (2014), http://dx.doi.org/10.1016/

http://dx.doi.org/10.1016/j.drudis.2014.07.008http://dx.doi.org/10.1016/j.drudis.2014.07.008

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DRUDIS 1465 1530 Rathkopf, D.E. et al. (2013) A phase I study of ARN-509, a novel antiandrogen,

in the treatment of castration-resistant prostate cancer. J. Clin. Oncol. 31,

35253530

31 Chan, S.C. et al. (2012) Androgen receptor splice variants activate androgen receptor

target genes and support aberrant prostate cancer cell growth independent

of canonical androgen receptor nuclear localization signal. J. Biol. Chem. 287,

1973619749Please cite this article in press as: Carver, B.S. Strategies for targeting the androgen rej.drudis.2014.07.00832 Watson, P.A. et al. (2010) Constitutively active androgen receptor splice variants

expressed in castration-resistant prostate cancer require full-length androgen

receptor. Proc. Natl. Acad. Sci. U. S. A. 107, 1675916765

33 Myung, J.K. et al. (2013) An androgen receptor N-terminal domain antagonist for

treating prostate cancer. J. Clin. Invest. 23, 29482960

34 Ravindranathan, P. et al. (2013) Peptidomimetic targeting of critical androgen

receptor-coregulator interactions in prostate cancer. Nat. Commun. 4, 1923ceptor axis in prostate cancer, Drug Discov Today (2014), http://dx.doi.org/10.1016/

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Strategies for targeting the androgen receptor axis in prostate cancerIntroductionCastrate-resistant prostate cancer maintains a functional AR axisMolecular alterations of AR in castrate-resistant prostate cancerAmplification and overexpression of AR in castrate-resistant prostate cancerAndrogen production in castrate-resistant prostate cancerTargeting the AR in castrate-resistant prostate cancerTargeting androgen production in castrate-resistant prostate cancerEmerging approaches to targeting AR in prostate cancer and concluding remarksConflict of interestReferences