recent developments in prostate cancer biomarker austin ...€¦ · according to prostate cancer...

Recent developments inprostate cancer biomarkerresearch: therapeuticimplicationsSujitra Detchokul & Albert G. Frauman

Clinical Pharmacology and Therapeutics Unit, Department of Medicine (Austin Health/Northern

Health), the University of Melbourne, Heidelberg, Victoria 3084, Australia

CorrespondenceProfessor Albert G. Frauman MD, FRACP,FACP, FACCP, Department of Medicine,Austin Campus, the University ofMelbourne, Clinical Pharmacology andTherapeutics Unit, Heidelberg, Victoria3084, Australia.Tel.: + 613 9496 5486Fax: + 613 9496 3510E-mail: albertf@unimelb.edu.au----------------------------------------------------------------------

Keywordsbiomarker, prostate cancer, review----------------------------------------------------------------------

Received31 March 2010

Accepted19 July 2010

This review aims to present an overview of recent clinical trials targeting biomarkers in advanced prostate cancer. We searchedClinicalTrials.gov for early phase clinical trials on treatments of prostate cancer that have been recently completed, are ongoing or areactively recruiting participants. Drug targets and their mechanism of actions were assessed and summarized. Trials were categorizedaccording to prostate cancer biomarkers that have potential as therapeutic targets. A total of 19 new therapeutic agents for thetreatment of prostate cancer are included in this review. Trials are summarized according to the targeted biomarkers and arecategorized into five therapeutic approaches: prostate cancer vaccine, epigenetic therapy, pro-apoptotic agents, prostate cancerantibodies and anti-angiogenesis approach. Some of the therapeutic agents reviewed showed promising results, warranting furtherinvestigation in late phase clinical trials. Recent novel prostate cancer biomarkers that made it through clinical trials and their relevanceas drug targets are summarized. This review emphasizes the importance of specific prostate cancer biomarkers and their potentials astargets of the disease. Some clinical trials of targeted treatments in prostate cancer show promising results. Better understanding ofdisease mechanisms should potentially lead to more specific treatments for individual patients.

Introduction

Prostate cancer and PSA screeningProstate cancer is among the most commonly diagnosedmale disease and remains a leading cause of death in mostWestern countries, especially in elderly men [1–3]. Morethan half of all men diagnosed with cancer are over the ageof 70 years, with prostate cancer constituting about 50% ofcancers in this age group [4].

Rapid increases in incidence rates for prostate cancer inthe past two decades have occurred in part due to thewidespread use of screening since the 1980s, by serumprostate-specific antigen (PSA), a glycoprotein producedby the prostate gland [5–8]. Whether PSA screening andearlier detection of prostate cancer has an impact on thedecline of mortality is still debated [9–12]. Recently, largescale studies from the US [13] and Europe [14] looking atcorrelation between PSA screening and prostate cancermortality have been published. In the US, they found nosignificant decline in mortality rate between patientsreceiving annual PSA screening and digital rectal examina-tion (DRE) and those receiving usual care which may some-times include screening [13]. However a study from

European countries found a weak association betweenincreased PSA screening and mortality rate [14]. There is,nonetheless, an urgent need for better biomarkers toreplace or work in conjunction with PSA screening, due tothe high prevalence of false positive and false negativerates seen with PSA alone [8].

Biomarkers leading to new therapeuticapproachesThe knowledge of biomarkers in cancer offers new hopefor more specific therapies and provides importantunderstanding of the factors influencing the aggressive-ness of prostate cancer and potential new treatments[15]. Molecular genetic approaches examining tumourgene expression profiling using microarrays have beenintroduced in recent years and analysis using a smallpanel of genes of interest has the potential for use inclinical practice to allow better diagnosis and classifica-tion of the disease, provide information on how each indi-vidual patient may respond to treatments and lead toreduced toxicity and identification of new therapeutics[16, 17]. We will review a number of biomarkers in pros-tate cancer which have involved development of targeted

British Journal of ClinicalPharmacology

DOI:10.1111/j.1365-2125.2010.03766.x

Br J Clin Pharmacol / 71:2 / 157–174 / 157© 2011 The AuthorsBritish Journal of Clinical Pharmacology © 2011 The British Pharmacological Society

therapies in animal and human trials. Figure 1 schemati-cally summarizes the function of these various biomark-ers. Table 1 summarizes these targets and ongoing clinicaltrials which will be discussed in the following section.Although, as mentioned above, PSA measurement haslimitations in prostate cancer management, most studieswe reviewed utilized PSA responses as an efficacy end-point. Some studies also used the RECIST system (toevaluate response rates of tumour lesions) [18].

Current clinical trials in prostate cancerbiomarker targetingProstate cancer vaccines Cancer vaccines stimulate sys-temic anti-tumour immune responses which may provide

reduced toxicities compared with traditional chemo-therapy. Patients who develop an androgen-independentprostate cancer after radiation therapy or hormone abla-tion therapy and those who have metastatic disease at thetime of diagnosis are much less likely to be cured.Thereforeit is crucial to identify markers early in the disease processthat might be able to distinguish between indolent andaggressive cancers [19–22]. The presence of markers thatare prostate-specific and prostate cancer-specific [23] suchas PSA,prostate specific membrane antigen (PSMA) (PSCA),and early prostate cancer antigen (EPCA) makes thempotential candidates for cancer vaccines.

Granulocyte-macrophage colony-stimulating factor(GM-CSF) vaccine or GVAX® is a promising approach for

Prostate tumour cell

Endothelial cell

mTOR

mTOR

HypoxiaGFs, glucose

PI3K

AKT/PKB

PTEN

Ras/Raf

GLUT1

VEGF

TGF-a

HIF 1a

TSC1/2

PDGF

Lymphoid organ

DC

RAD001

CCI779

PDGFR

VEGFR

Sunitinib

Bevacizumab

Imatinib

DC

AR

AR

AR

Androgen

ARAR PP

PSAPSA

PSA

survivin

Bcl-2

Cyt. c

Caspase

YM155

G3139

AT-101

PSMA

MLN2704

177-Lu-J591

M

177JuDM1

177JuDM1

HDAC

inhibitors

Cancer Vaccines:

PCa cells(+cytokines),

Adenovirus-mediated IL-12

PSMA

PCaGM-CSF

PCaIL-2

PCa

IFN-g

PCa

5 ’3 ’

mRNA

Ad.hIL-12

B

DC

PSCA

STEAP

CTLCTL

TH

TH

5 ’3 ’

5 ’3 ’

mRNAs

vaccines

(PCa Ag)

Figure 1Site of actions of drugs that are currently in clinical trials for treatment of prostate cancer and target biomarkers and their roles in prostate cancer.[Experimental therapeutics: RAD001, CCI779, mRNAs vaccines, MLN2704, 177-Lu-J591, YM155, HDAC inhibitors, G3139, AT-101, bevacizumab, sunitinib,imatinib and cancer vaccines are indicated as RED diamonds], lymphoid cells are indicated as B ( B ) for B lymphocyte; CTL ( C ) for cytotoxic T lympho-cytes); M ( M ) for macrophage; TH ( T ) for T helper cells and DC ( ) for dendritic cells; P indicates phosphorylation. (For others see ‘abbreviations andacronyms’ listing for definitions of targets under study

S. Detchokul & A. G. Frauman

158 / 71:2 / Br J Clin Pharmacol

Tab

le1

Cu

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td

rug

sin

clin

ical

tria

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ent

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pro

stat

eca

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ical

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dy

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ren

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)

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gs

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ets

Mo

de

of

acti

on

Stag

eo

fd

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men

t(T

rial

ph

ase)

Effi

cacy

Do

selim

itin

gto

xici

ties

(DLT

)Tr

eatm

ent

mo

dal

ity

Inte

nt

of

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Clin

ical

tria

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Are

spo

nse

An

ti-t

um

ou

rre

spo

nse

(REC

IST

[18]

)

GV

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®va

ccin

eG

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SF•

Prol

onge

dim

mun

ityag

ains

tPC

ace

llsvi

aD

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ffer

entia

tion

and

prol

ifera

tion

•Sp

ecifi

cto

PCa

cells

I,II

Phas

eI/I

I•

Ove

rall

med

ian

PSA

DT

incr

ease

dco

mpa

red

with

pre-

trea

tmen

t[3

5]•

8/19

(42%

)pa

tient

sha

dst

able

PSA

durin

gtr

eatm

ent

perio

d[35

]•

16/2

1(76

%)

patie

nts

had

decr

ease

dPS

Apo

st-t

reat

men

ts[3

4]•

42/8

0(5

2%)

patie

nts

that

had

decr

ease

PSA

conc

entr

atio

nsha

dlo

nger

surv

ival

s[3

3]

Phas

eI/I

I•

T-ce

llan

dB-

cell

stim

ulat

ions

[34,

35]

•28

/80

patie

nts

had

SD[3

3]

DLT

not

reac

hed

inan

ytr

ials

Sing

le/c

ombi

natio

n(A

DT)

Palli

atio

n[3

3–35

][1

54,

155]

RN

Act

ive®

-der

ived

PCa

vacc

ine

(CV

9103

)

PSA

,PS

MA

,PS

CA

and

STEA

P

•D

irect

anti-

tum

our

activ

ityvi

ade

liver

yof

mRN

Aen

codi

ngpr

osta

te-s

peci

ficA

g

I,II

N/A

N/A

N/A

Sing

lePa

lliat

ion

[37]

[38,

39]

IL-2

-IFN

-g-s

ecre

tin

gtu

mo

ur

vacc

ine

IL-2

and

IFN

-g

•Sp

ecifi

can

ti-tu

mou

rre

spon

ses

•En

hanc

ing

Ag-

pres

entin

gce

llsan

dT-

cells

resp

onse

sto

tum

our

Ags

I,II

Phas

eI[

41]

•2/

6pa

tient

sha

d>5

0%PS

Ade

clin

e•

2/6

patie

nts

had

PSA

stab

iliza

tion

Phas

eI/I

I[40

]•

22/3

0pa

tient

sha

din

crea

sed

PSA

DT

com

pare

dw

ithpr

e-tr

eatm

ent

•12

/30

had

plat

eau

PSA

for

ape

riod

of12

wee

ks

Phas

eI[

41]

•Im

mun

ogen

icA

gPS

GR-

1,ST

EAP,

PSA

,PR

AM

E(5

/6pa

tient

s)•

Imm

unog

enic

Ag

PSC

A,

PSM

Aan

dEp

CA

M(3

/6pa

tient

s)Ph

ase

I/II[

40]

•Im

mun

ogen

icA

gsin

clud

ing

surv

ivin

,PS

CA

,PS

MA

,PS

A,

STEA

P,PA

Pan

dEp

-2H

Both

tria

lsha

dT-

cell

resp

onse

agai

nst

PCa

Ag

(but

was

not

corr

elat

edw

ithPS

Are

spon

se)

DLT

isno

tre

ache

din

any

tria

lsSi

ngle

Palli

atio

n[4

0,41

][3

6]

Ad

eno

viru

s-m

edia

ted

IL-1

2g

ene

del

iver

yan

dPS

MA

-pu

lsed

PBM

Cw

ith

reco

mb

inan

tIL

-12

IL-1

2ge

ne•

Incr

ease

tum

our

cells

susc

eptib

ility

tocy

toto

xic

Tce

lls

IN

/AN

/AN

/ASi

ngle

Palli

atio

n[4

2][5

1,52

]

Vo

rin

ost

at(S

AH

A),

pan

ob

ino

stat

,b

elin

ost

at(P

XD

101)

,va

lpro

icac

idan

dro

mid

epsi

n(F

K22

8)

HD

AC

s•

Epig

enet

icth

erap

y•

Prev

entio

nof

gene

mod

ifica

tion

prom

otin

gca

ncer

surv

ival

I,II

Vorin

osta

tPh

ase

ISi

ngle

agen

t[6

6,68

]•

Tria

lsof

com

bine

dso

lidan

dha

emat

olog

ical

mal

igna

ncie

s•

PSA

conc

entr

atio

nsw

ere

not

dete

rmin

edPa

nobi

nost

atPh

ase

IC

ombi

natio

n[7

1]A

llpa

tient

sre

ceiv

ing

pano

bino

stat

alon

eha

dPS

Apr

ogre

ssio

n

Vorin

osta

tPh

ase

ISi

ngle

agen

t[6

6,68

]•

PCa

patie

nts

did

not

have

anti-

tum

our

resp

onse

Pano

bino

stat

Phas

eI

Com

bina

tion

[71]

•2/

7pa

tient

sre

ceiv

ing

pano

bino

stat

+do

ceta

xel

had

PR

Vorin

osta

tPh

ase

ISi

ngle

agen

t[6

6,68

]•

Gra

de4

leuk

open

ia•

Gra

de3⁄4

thro

mbo

cyto

peni

a•

Gra

de4

neut

rope

nia

Pano

bino

stat

Phas

eI

Com

bina

tion

[71]

•G

rade

3ne

utro

peni

a•

Gra

de3

dysp

nea

Sing

le/C

ombi

natio

n(c

hem

othe

ra-p

y,A

DT,

isot

retin

oin

and

beva

cizu

mab

)

Palli

atio

n[6

6–71

,15

6][5

3–60

,15

7,15

8]

Prostate cancer biomarkers: therapeutic implications

Br J Clin Pharmacol / 71:2 / 159

Tab

le1

Co

nti

nu

ed

Dru

gs

Targ

ets

Mo

de

of

acti

on

Stag

eo

fd

evel

op

men

t(T

rial

ph

ase)

Effi

cacy

Do

selim

itin

gto

xici

ties

(DLT

)Tr

eatm

ent

mo

dal

ity

Inte

nt

of

trea

tmen

tR

ef.

Clin

ical

tria

lsPS

Are

spo

nse

An

ti-t

um

ou

rre

spo

nse

(REC

IST

[18]

)

Co

nt’

d•

5/8

patie

nts

rece

ivin

gpa

nobi

nost

at+

doce

taxe

lha

d�

50%

PSA

decl

ine

Phas

eIb

Com

bina

tion

[69]

•10

/18

patie

nts

had

decl

ine

PSA

(7pa

tient

s>5

0%de

clin

e)Be

linos

tat

Phas

eI

Sing

leag

ent

[67]

•PS

Aco

ncen

trat

ions

not

mea

sure

d

(Incl

udin

g1

patie

ntw

hoha

d�

50%

PSA

decl

ine

•4/

7pa

tient

sha

dre

ceiv

ing

pano

bino

stat

+do

ceta

xel

had

SDPh

ase

IbC

ombi

natio

n[6

9]•

2/13

patie

nts

had

PR•

6/13

patie

nts

had

SDBe

linos

tat

Phas

eI

Sing

leag

ent

[67]

•18

/46

patie

nts

had

SD•

12/2

4(M

TD)

patie

nts

had

SD

Phas

eIb

Com

bina

tion

[69]

•G

rade

4br

adyc

ardi

a•

Gra

de4

neut

rope

nia

Belin

osta

tPh

ase

ISi

ngle

agen

t[6

7]•

Gra

de3

fatig

ue•

Gra

de3

atria

lfibr

illat

ion

Rom

idep

sin

Phas

eII

Sing

leag

ent

[70]

•2/

35ha

d�

50%

PSA

decl

ine

PSA

resp

onse

rate

of5.

7%

Rom

idep

sin

Phas

eII

Sing

leag

ent

[70]

2/35

patie

nts

had

PR

•G

rade

3di

arrh

oea

•G

rade

2na

usea

/vom

iting

Rom

idep

sin

Phas

eII

Sing

leag

ent

[70]

DLT

was

not

reac

hed

due

toea

rlytr

ialc

losu

re

Ob

limer

sen

sod

ium

(G31

39)

and

R-(

-)-g

oss

ypo

lac

etic

acid

(AT-

101)

Bcl-2

•Ta

rget

ing

anti-

apop

totic

Bcl-2

prot

ein

•In

crea

sesu

scep

tibili

tyof

canc

erce

llsto

cyto

toxi

cdr

ugs

and

radi

othe

rapy

I,II

Obl

imer

sen

Com

bina

tion

•C

ontr

adic

ting

resu

ltson

PSA

resp

onse

s[7

9,80

]•

14/2

7pa

tient

sha

dPS

Are

spon

se(6

patie

nts

had

�80

%PS

Ade

clin

e)[7

9]•

PSA

decl

ine

of�

30%

was

not

reac

hed

[80]

Obl

imer

sen

Com

bina

tion

•C

ontr

adic

ting

resu

lts[7

9,80

]•

4/12

had

PR[7

9]•

Doc

etax

el-o

blim

erse

nan

ddo

ceta

xela

lone

show

edsi

mila

rcl

inic

alre

spon

ses

[80]

Obl

imer

sen

•G

rade

3⁄4

neut

rope

nia

•G

rade

3⁄4

leuk

open

ia•

Gra

de3⁄4

fatig

ue

Com

bina

tion

(Che

mot

hera

pyan

dA

DT)

Palli

atio

n[7

9,80

,84

,85

][7

8,83

,15

9,16

0]

AT1

01Si

ngle

agen

t[8

4]•

2/23

(8%

)pa

tient

sha

d�

50%

decl

ine

inPS

Aco

ncen

trat

ions

Com

bina

tion

[85]

•14

/20

(70%

)pa

tient

sha

d�

50%

decl

ine

inPS

Aco

ncen

trat

ions

AT1

01Si

ngle

agen

t[8

4]•

2/19

patie

nts

SDC

ombi

natio

n[8

5]•

50%

PRle

vels

AT1

01•

Gra

de3

smal

lint

estin

alob

stru

ctio

n•

Gra

de3

gast

roin

test

inal

toxi

citie

s

YM

155

Surv

ivin

•Pr

o-ap

opto

ticag

ents

•Bl

ock

apop

tosi

sin

hibi

tor

prot

ein,

surv

ivin

I,II

•2/

9(2

2%)

PCa

patie

nts

had

decl

ine

PSA

conc

entr

atio

ns

•O

nly

PSA

conc

entr

atio

nsw

ere

dete

rmin

edfo

rPC

apa

tient

s

•In

crea

secr

eatin

ine

conc

entr

atio

ns•

Gra

de3⁄4

neut

rope

nia

•G

rade

3th

rom

bocy

tope

nia

Sing

le/C

ombi

natio

n(C

hem

othe

rapy

)Pa

lliat

ion

[89]

[90,

91]

MLN

2704

and

177L

u-J

591

PSM

A•

PCa

Ab

•A

b-di

rect

edcy

toto

xic

drug

and

radi

oiso

tope

s

I,II

MLN

2704

Sing

leag

ent

[94]

•2/

23(8

%)

with

PSA

decl

ine

of�

50%

MLN

2704

Sing

leag

ent

[94]

•40

%SD

MLN

2704

•U

ncom

plic

ated

febr

ilene

utro

peni

a

Sing

le/C

ombi

natio

n(1

77Lu

-J59

1w

ithch

emot

hera

pyan

dA

DT)

Palli

atio

n[9

3,94

,10

0,10

1][9

5–99

,16

1,16

2]



Tab

le1

Co

nti

nu

ed

Co

nt’

d17

7Lu-

J591

Sing

leag

ent

•2/

29ha

d70

–80%

decl

ine

inPS

Aco

ncen

trat

ions

[101

]•

6/29

had

PSA

stab

iliza

tion

[101

]•

4/35

had

�50

%PS

Ade

clin

e[1

00]

•16

/35

had

PSA

stab

iliza

tion

[100

]

177L

u-J5

91Si

ngle

agen

t2/

12pa

tient

sob

ject

ive

resp

onse

s[10

1]

177L

u-J5

91•

Gra

de4

thro

mbo

cyto

peni

a•

Gra

de4

neut

rope

nia

Bev

aciz

um

ab(A

vast

in)

VEG

F•

Ant

i-ang

ioge

nesi

sI,

IIC

ombi

natio

n•

11/2

0(5

5%)

patie

nts

has

maj

orPS

Are

spon

se

Com

bina

tion

•2/

8pa

tient

sha

dSD

•3/

8pa

tient

sha

dPR

•3/

8pa

tient

sha

dPD

•G

rade

3⁄4

neut

rope

nia

•G

rade

3⁄4

thro

mbo

cyto

peni

a

Sing

le/C

ombi

natio

n(C

hem

othe

rapy

,A

DT,

mTO

Rin

hibi

tor)

Palli

atio

nan

dpr

even

tion

[146

][1

11,

112,

142,

147,

148,

163–

165]

Imat

inib

mes

ylat

e(G

leev

ec®

)PD

GFR

•A

nti-a

ngio

gene

sis

I,II

Sing

leag

ent

•1/

19pa

tient

sha

d�

50%

decl

ine

and

2/19

had

ade

clin

eof

<50%

[118

]•

Med

ian

PSA

DT

(16/

19pa

tient

s)w

ere

not

diff

eren

tpr

e-an

dpo

st-t

reat

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prostate cancer [24]. This vaccine involves geneticallymodified irradiated prostate cancer cells expressing thecytokine, GM-CSF which is a known mediator of immunesystem activation [25]. In mice, irradiated tumour cellsexpressing GM-CSF need CD4+ and CD8+ T-cells forimmune activation and result in a long lasting and specificimmune response [26]. In 2000, successful phase I/II trialsusing dendritic cells (DC) with encoding fusion proteins ofprostatic acid phosphatase (PAP) and GM-CSF in hormone-refractory prostate cancer patients demonstrated anti-PAPimmune responses in all patients. Almost half of partici-pants involved had a decline in PSA concentrations, withno major adverse effects [27]. The mechanism of action ofthis immunotherapy involves DC (adaptive) immuneresponses to tumour cell antigens, thus promoting differ-entiation of bone marrow-derived progenitors into DCs atthe local injection site [28]. GM-CSF can reverse tumourtolerance and produce anti-tumour responses by initiatingbone marrow-derived progenitor differentiation into DCsand DC proliferation [24, 28, 29].1

Hege et al. [28] have summarized clinical trials thatcombined immunotherapy with other treatments toenhance the effectiveness of anti-tumour activity and thisincludes the use of CD40 and Toll-like receptors (TLRs) forDC activation, anti-CTLA4 and anti-CD25 antibodies. Theseapproaches attempt to inhibit down-modulation of T-cellresponses, vascular endothelial growth factor (VEGF)blockade to prevent inhibitory effects of the VEGF recep-tor, and interferon (IFN)-a for promotion of immunomodu-latory responses. Furthermore, chemotherapy, for examplewith docetaxel, a cytotoxic anti-microtubule agent andanti-androgen therapy, has been combined with cancervaccines in clinical trials to see if these more traditionaltreatments can enhance anti-tumour responses [30, 31].

An early phase I trial of eight prostate cancer patientsinvolved treatment with autologous cancer vaccine pre-pared from the patients’ own prostate tumours takenduring prostatectomy, which were then irradiated andengineered to express GM-CSF [32]. This trial evaluatedpatients’ T- and B-cell immune responses at the injectionsites, hypersensitivity against the un-transduced autolo-gous tumour cells and antibodies against tumour antigensin the serum. There were increased immune responses atthe vaccination site including CD4�, CD8� T-cells,T helpercells, macrophages and DCs. Three out of eight patientshad antibodies specific to prostate cancer antigens.Clinicaltrial phase I/II studies using allogeneic human GM-CSFgene transduced irradiated prostate tumour cell linesadministered via intradermal injection have demonstratedearly evidence of safety and clinical activity,showing dose–response immune responses and good tolerance in

patients with metastatic hormone-refractory prostatecancer [33–35].

RNActive®-Derived Prostate Cancer Vaccine, CV9103. isanother promising immunotherapy vaccine for prostatecancer which derives from mRNA encoding prostate-specific antigens which have been modified to maintainstability (PSA, PSMA, PSCA and six-transmembrane epithe-lial antigen of the prostate [STEAP]) [36].The mechanism ofaction involves stimulation of cytotoxic T lymphocytes bygene therapy vehicle mRNAs to respond against PSA-,PSMA-, PSCA- and STEAP-expressing prostate tumour cells[37]. The use of naked mRNA vectors has been recentlydeveloped and engineered to overcome the issue of insta-bility of mRNA leading to rapid digestion within the body.This mRNA technology is now being tested in prostatecancer and non-small cell lung cancer. Current open clini-cal trials phase I/IIa and II are now recruiting participantswith evidence of hormone refractory prostate cancershowing increasing concentrations of PSA despitehormone deprivation therapy, using CV9103 delivery viamultiple intradermal injections [38, 39].

Interleukin-2 (IL-2)-interferon-gamma (IFN-g)-secretingallogenic tumour vaccine derived from allogeneic prostatecancer cell lines with recombinant human IL-2 and IFN-ghave been involved in early clinical trials via multiple intra-dermal injections [36, 40, 41] and have shown prostatecancer antigen-specific T-cell responses (reactivity againstpeptides PSMA, PAP, survivin, PCTA and PSA), but assess-ment of effectiveness of this combination of the two cytok-ines requires further investigation.

Pre-clinical data using adult bone marrow cells as adelivery vehicle for Il-12 genes showed satisfactory anti-metastatic effects (and prolonged survival in a mousemodel with metastatic prostate cancer, with elevatedlevels of CD4+ and CD8+ T-cells [42, 43]. Adenovirus pre-infected with Il-12 into the transgenic adenocarcinoma ofthe mouse prostate (TRAMP) model of prostate canceralso results in tumour-specific immune responses andanti-tumour activity [44, 45]. An orthotopic mouse modelof prostate cancer treated with Il-12 recombinant adenovi-ral vector transduced macrophages survived longer thancontrol treated mice [46]. Although, specific anti-tumourand anti-metastatic activity was seen, phase I trials involv-ing other cancers such as advanced digestive tumours,ovarian cancer, renal cell cancer and metastatic mela-noma, whilst encouraging in terms of drug safety, did notshow anti-tumour activity [47–50]. A current phase I trial ofIl-12 for patients with recurrent non-metastatic prostatecancer after radiation therapy is now ongoing [51]. Aphase II trial involving recombinant Il-12 transduced intoPSMA-pulsed autologous peripheral blood mononuclearcells (PBMC) in metastatic prostate cancer is also ongoing[52].

Epigenetic therapy Early phase clinical trials for histonedeacetylase (HDAC) inhibitors in a wide range of solid

1Provenge (sipuleucel-T), autologous CD54+ cells activated with PAP-GM-CSF, has recently been approved by the US FDA for the treatment ofasymptomatic or minimally symptomatic metastatic hormone refractoryprostate cancer.



tumours including prostate cancer have involved suberoy-lanilide hydroxamic acid (SAHA) or vorinostat [53, 54],LBH589 (panobinostat) [55, 56], PXD101 (belinostat) [57],valproic acid [58, 59] and FK228 (romidepsin) [60]. Themechanism of action is via direct inhibition of acetylationor methylation of histones affecting cancer-related geneexpression and may also be via an action through non-histone proteins such as p53, heat shock protein 90(Hsp90) and the androgen receptor, which leads to activa-tion of transcription of certain genes [61–65]. These earlyphase trials showed satisfactory tolerance, with resultsexamining serum PSA and acetylated histones (measure-ment of accumulated acetylated histones) across varioussolid tumour patients and provided good rationale toproceed to further clinical trials. Some of these trialsrecruited a wide range of patients with solid tumours, andanti-tumour activities were measured via clinical examina-tions that were analysed as partial response, completeresponse or stable disease [66–68]. PSA concentrationswere measured for those trials that involved castrate-resistant prostate cancer patients and the reduction in PSAconcentrations of more that 50% from baseline level wasconsidered to have major anti-tumour activity [69–71].Measurements of acetylated histones were carried out forall trials via either Western blotting, immunohistochemis-try or enzyme immunoassay (ELISA). Other effects of thedrugs i.e. pro-apoptitic activities were measured via con-current monitoring of apoptotic markers in the blood.

Clinical trials of PXD101 and SAHA showed good toler-ance, with a maximum tolerated dose determined to be1000 mg m-2 day-1 and 400 mg day-1, respectively, andboth trials showed dose-dependent histone hyperacetyla-tion [66–68]. These trials in patients with advanced solidtumours (and haematological malignancies for SAHAtrials) showed some anti-tumour activity (i.e. tumourregression, stable disease and tumour related pain) butthis was not evident in patients with advanced prostatecancer. Trials of panobinostat showed impressive anti-tumour effects with more than 50% of patients receivingpanobinostat in combination with docetaxel or docetaxel/prednisone having �50% decline in PSA concentrations, incontrast to those receiving panobinostat alone, wherealmost all patients had progressive disease despite dose-related increase histone acetylation [69, 71]. While thesetrials obtained valuable information on drug safety anddose-limiting toxicities, correlation between levels ofacetylated histones and disease progression could not beestablished. This may suggest the existence of a subpopu-lation of prostate cancer cells that do not respond toparticular HDAC inhibition and therefore implicates nar-rowing of a selective group of responsive patients withinchemo-naive patients.

The exact mechanism by which HDAC inhibitorsinduces tumour differentiation, cell cycle arrest andenhancing tumour cell sensitivity to chemotherapy is yetto be elucidated. Therefore each HDAC inhibitor may have

different effects on prostate cancer [72]. Some of the trialsmentioned above resulted in withdrawal of patients fromthe studies due to ongoing toxicities i.e. gastrointestinaltoxic effects including nausea, diarrhoea and vomiting.These early trials suggest that the use of HDAC inhibitors incombination with other therapies may minimize drug-related toxicities. Careful selection of patients to enter thetrials and drugs to be used for advanced prostate cancer inthe clinical trials may therefore give more informationregarding risk-benefit assessment of these compounds.

Pro-apoptotic agents Bcl-2 modulators Ursolic acid, apentacyclic triterpenoid compound [73, 74] and the CXCchemokine receptor-4 (CXCR4) antagonist, CTCE-9908 [75],down-regulate Bcl-2 resulting in induction of apoptosis.However, recent findings from Nariculam et al. [76] demon-strate that Bcl-2 and p53, although overexpressed in local-ized prostate cancer, were not associated with clinicaloutcomes. Nevertheless, Bcl-2 is a potential target and hasbeen assessed in clinical trials. For example, oblimersensodium (G3139, Bcl-2 antisense oligonucleotide) therapytargets the Bcl-2 initiation codon region of Bcl-2 mRNA anddown-regulates mRNA expression [77, 78]. A trial of G3139in combination with docetaxel suggested an encouragingcorrelation between steady-state concentrations and PSAdecline, with no serious toxicities reported [79]. However,another trial treating patients with oblimersen-docetaxelcombination showed increased toxicities (40% had majortoxic events compared with 22% in the docetaxel group)and did not incur better outcomes than docetaxel treat-ment alone [80]. A more recent study using microarray toevaluate the effects of G3139 and the effects of Bcl-2silencing via small interfering RNA (siRNA) on gene profil-ing of PC-3 cell lines has found that the apoptotic effectof G3139 was a result of an off-target response, viaup-regulation of growth-inhibitory proteins, rather than ofBcl-2 silencing alone (both treatments showed similarBcl-2 knock down) [77].This is important as treatment withBcl-2 siRNA alone in metastatic prostate cancer cell linesdid not induce apoptosis as seen with cells treated withG3139 [77]. Furthermore, although there were some anti-tumour responses as a result of targeting Bcl-2, severalissues still need to be addressed. Marked variation inpatients’ responses to different concentrations ofoblimersen was a major factor in defining effective dosesfor maximal response. Thus assessment of specific mecha-nisms by which oblimersen induces apoptosis will need tobe evaluated to fully understand and predict patients’responses and clinical adverse effects.

Another drug that is in clinical trials targeting Bcl-2 isthe small molecule inhibitor AT-101 [81–83]. In contrast toG3139, AT-101 targets the Bcl-2 homologous (BH) region 3of Bcl-2 and when given alone, there was satisfactory tol-erance in most castrate-resistance prostate cancerpatients, with some gastrointestinal toxicities leading toreduction in dosage [84]. Preliminary results of phase I/II



trials using a combination of AT-101, docetaxel and pred-nisone showed 70% (14/20) of prostate cancer patientswith a �50% PSA decline and 54% (6/11 patients withmeasurable disease) having partial responses by RECISTcriteria (Response Evaluation Criteria in Solid Tumors) [18],thus warranting further assessment of this agent [85].AT-101 may be a better candidate to target Bcl-2 as com-bination with traditional docetaxel did not result inincreased toxicities and these trials were given a moreusual dose regimen of 75 mg m-2 docetaxel unlike G3139trials where docetaxel had to be reduced (75 to 60 andthen to 45 mg m-2) due to ongoing toxicities [80, 85].

Survivin modulators Survivin is a member of the inhibitorsof apoptosis (IAPs) gene family and its expression is seenduring fetal development and not in normal, terminallydifferentiated adult human tissues [86]. However, survivinover-expression is seen in various adenocarcinomasincluding prostate [86]. Moreover, increased expression isassociated with disease progression after radical prostate-ctomy [87]. Pre-clinical data have demonstrated thatYM155, a small molecule survivin suppressant, promotedapoptosis in vitro and in an in vivo xenograft mouse model,using hormone-refractory prostate cancer cell lines andthat this apoptotic effect was not significantly related toother IAPs or Bcl-2 related proteins [88]. YM155 has nowbeen in early clinical trials and one single-agent trial invarious advanced cancers showed some anti-tumour activ-ity (two out of nine prostate cancer patients had a declinein PSA concentrations) [89]. Other recently completedearly phase trials according to ClinicalTrials.gov (resultsunavailable) are either YM155 single agent in advancedcancers or YM155 in combination with docetaxel inhormone refractory prostate cancer patients [90, 91].

Prostate cancer antibodies Immunoconjugates consistingof a humanized monoclonal Ab which is directed againstprostate-specific membrane antigen (PSMA) have beeninvestigated in prostate cancer [92]. One of the currentdrugs in clinical trials is MLN2704. MLN2704 is an immuno-conjugate consisting of humanized monoclonal Abdirected against PSMA (named MLN591 Ab) whichwas linked to a maytansinoid (DM1). DM1, a potentmicrotubule-depolymerizing drug, is an analogue of may-tansine, a naturally occurring ansa macrolide [93]. Themonoclonal antibody moiety of MLN2704 binds to tumourcells expressing PSMA and is then internalized into thetumour cell, where the DM1 maytansinoid moiety binds totubulin and inhibits tubulin polymerization and microtu-bule assembly, resulting in a disruption of microtubuleactivity, cell division and cell death. Pre-clinical datashowed MLN2704 efficiency in anti-tumour activity in amouse xenograft model, in a dose- and schedule-dependent manner [93]. Early phase I/II trials usingMLN2704 showed acceptable safety (no antibodyresponses to either MLN2704, MLN591 or DM1) with minor

grade toxicities such as fatigue and headache with only1/23 patients reaching dose-limiting toxicity of uncompli-cated febrile neutropenia, but neuropathy was observed in35% of patients [94]. The efficacy of MLN2704 was mea-sured by PSA concentrations and tumour regression. Twopatients sustained �50% decline in PSA concentrationscompared with baseline and six other patients treated atdoses �156 mg m-2 sustained stable PSA concentrationsfor up to 86 days. Of 10 assessable patients, four had stabledisease up to a dose of 343 mg m-2 and one patient receiv-ing 264 mg m-2 had a partial response. This trial provideduseful information regarding the dosage and immuno-genic responses to the drug. Further trials are ongoingusing MLN2704 alone in progressive metastatic prostatecancer patients [95–97].

Radiolabelled monoclonal Ab HuJ591-GS (177Lu-J591)derived from J591, an immunoglobulin G (IgG) mono-clonal Ab targeting the extracellular domain of PSMA(tagged with radionuclide lutetium-177) is currentlyunder phase I/II clinical trials [98, 99]. However someresults from earlier phase I trials determined dose-limitingtoxicity (including grade 4 neutropenia, severe thromb-ocytopenia, and other severe non-haematologic toxici-ties), In another trial, some patients had more than70–80% decline in PSA concentrations which lasted up to3–8 months and there was a strong correlation betweenPSA concentrations and measurable disease responses[100, 101]. Both trials did not show anti-immunogenicresponses to the drugs.

These trials warrant the potential further use of PSMAas a biomarker for targeted treatments in prostate cancer,suggesting efficacy together with safety and lack of immu-nogenic responses to the PSMA antibodies, foreshadowingthe need for further clinical assessment.

Anti-angiogenesis approaches Vascular endothelialgrowth factor (VEGF) is currently being targeted as a treat-ment for cancer together with traditional cancer treat-ments. Expression levels of VEGF, an angiogenic stimulator,are elevated in prostate cancer and PIN and found to bedown-regulated by androgen deprivation, resulting inchanges in patterns of vascularization [102]. In addition,Ferrer et al. [103] found that there was no or diminishedVEGF and IL-8 expression in BPH and normal prostatetissue, whilst expression was also reduced in higher gradesof prostate cancer. Overexpression of angiogenic factors inmalignant tissues, particularly VEGF is proposed to bemediated largely by hypoxia-inducible factor-1 alpha(HIF-1 a), a transcription factor [104]. As a response tooxygen deprivation (hypoxia), HIF-1 heterodimer complexis formed and consists of HIF-1a and HIF-1b transcriptionfactors which in turn regulate activation of angiogenesis tohelp restore oxygen homeostasis [105]. HIF-1a is found tobe overexpressed in prostate cancer specimens comparedwith BPH, but this overexpression is not associated withprogression of the disease [106, 107]. HIF-1a expression is



not seen in normal prostate tissues [107, 108]. Targeting ofhypoxia-induced angiogenesis with HDAC inhibitors thatinhibit HIF-1a activity and hence reduce expression ofVEGF (and basic fibroblast growth factor [bFGF]) are cur-rently being investigated in prostate cancer [105]. Otherdrugs targeting VEGF in phase I and II clinical trials arebevacizumab, a humanized anti-VEGF antibody, which hasbeen approved for treatments of other cancers such asmetastatic breast cancer, non-small-cell lung cancer, glio-blastoma, renal cell carcinoma and colorectal cancers [58,109, 110]. Bevacizumab in combination with docetaxel iswell tolerated and approximately 50% of patients haddecreased concentrations of PSA in a phase II clinical trialfor metastatic hormone refractory prostate cancer [111,112].

Platelet derived growth factor receptor (PDGFR) andplatelet derived growth factor (PDGF) PDGFR and PDGFare frequently expressed in primary and metastatic pros-tate cancer [113, 114] and PDGF A and its receptor PDGFRalpha are expressed in PIN, a likely precursor of prostatecancer [115].This suggests that inhibition of PDGFR may beof therapeutic benefit to advanced prostate cancerpatients. Imatinib mesylate is a potent inhibitor of PDGFRand has been approved by the FDA for the treatment ofchronic myelogenous leukaemia and metastatic gas-trointestinal stromal cancers [116]. Treatment with ima-tinib in an experimental prostate cancer mouse model wasbetter than paclitaxel alone in reducing bone metastasesbut the anti-tumour effect was strongest with the combi-nation of both [117]. However, several phase II trials evalu-ating imatinib mesylate alone did not show decline in PSAconcentrations and, with one study, severe side effects(grade 3 and 4 haematological toxicities, neutropenia andlymphopenia, or recurrent grade 1 and 2 non-haematological toxicities) had lead to early closure [118–120], although there are several trials that are underway[121–123]. Another drug that inhibits both PDGFR andVEGFR is sunitinib malate, a multiple receptor tyrosinekinase inhibitor [124], which is currently an approved treat-ment for stomach cancer and gastrointestinal stromalcancer [125]. A phase II trial with only sunitinib given totwo groups of patients (docetaxel-resistant prostatecancer patients and patients with no prior treatment)showed no significant decline in PSA levels in the majorityof patients but serum angiogenesis biomarkers i.e. VEGFRand PDGFaa, a member of PDGF family, confirmed effectsof sunitinib malate upon angiogenesis factors [124]. Eventhough this trial did not reach the expected PSA responses(confirmed �50% decline in PSA concentrations frombaseline), an interesting point from this trial was that suni-tinib affected PSA changes in both group of patients simi-larly (only one patient per group had a major PSA responseand there were similar numbers of patients with stable PSAfor up to 12 weeks post-treatment). Another trial targetingmetastatic castration-resistant prostate cancer patients

with prior docetaxel treatment demonstrated declines inPSA in 30% of the patients, but half of the participantsdiscontinued the drug due to severe grade 3–4 toxicities offatigue, anorexia, nausea and leukopenia and there weretwo deaths deemed to be related to the study [126].Actively recruiting phase II clinical trials are ongoing forsunitinib malate with either combination with taxotere(docetaxel/prednisone) [127], hormone ablation therapy[128] or radiation therapy [129].

mTOR (mammalian target of rapamycin) mTOR is aprotein kinase that regulates cell growth, cell proliferation,cell motility, cell survival and protein synthesis and mTORpathway proteins are overexpressed in primary prostatecancer compared with high-grade PIN and BPH tissues[130], expression being correlated with aggressiveness ofthe disease [131]. The loss of phosphatase and tensinhomolog (PTEN) tumour suppressor gene indicating pro-gression towards the malignant form leads to activation ofthe phosphatidylinositol 3-kinase (PI3K)/Akt (proteinkinase B family)/mTOR signalling pathway [132]. PTEN iscorrelated with increased in mTOR signalling pathwaymarkers [131] and oncogenic Akt activation in prostatecancer [133]. In addition, PTEN expression is often lostwhere Bcl-2 is often overexpressed as the diseaseprogresses [134, 135]. One study demonstrated that resis-tance to apoptosis via an mTOR pathway inhibitor can be aresponse mediated by HIF-1a regulation and Bcl-2up-regulation, suggesting a combination of a mTOR inhibi-tor and Bcl-2 inhibitor to prevent mTOR inhibitor resis-tance may be useful [136]. Pre-clinical data suggest acombination of mTOR inhibitor and chemotherapy mayinhibit growth of prostate cancer and prolong survival in axenograft model [137]. Also, a combination of a mTORinhibitor and anti-androgen therapy may benefit somepatients as there is evidence that androgen receptorstimulation promotes mTOR activation but only at a con-centration of up to ~1 nmol l-1 [138] and androgen depri-vation has no effect on mTOR activation in PTEN-deficientmice [139]. In vivo experiments using an androgen-independent metastatic cell line in a xenograft mousemodel suggested that inhibition of growth via mTORinhibitor was a result of re-population of PTEN-deficientcancer cells [137]. Pre-clinical data of RAD001 (everolimus)treatment in mice implanted with androgen-independentcell lines with mutated PTEN resulted in reduction of bonemetastases and serum PSA concentrations and the resultwas enhanced with a combination of RAD001, docetaxeland zoledronic acid [140]. A pilot study using rapamycin(sirolimus) in 13 hormone-refractory prostate cancerpatients resulted in some patients (1/13) with a 50% PSAdecline and stable disease (4/13), with mean survival timeafter treatments being nearly 24 months [141]. mTORinhibitors, everolimus and temsirolimus are now in phase IIclinical trials in patients with castration-resistant meta-static prostate cancer [111, 142–145].



Discussion

Treatment for hormone-refractory prostate cancer includesdocetaxel-based chemotherapy regimens. However thereare very limited choices of treatment if there is an inad-equate response to this approach. The majority of clinicaltrials reviewed focused on hormone-refractory prostatecancer patients. However more clinical trials recruitingpatients prior to any treatment may also be valuable instudying initial responses of cancer cells to each drug.

The present review focuses on new agents adminis-tered in conjunction with traditional systemic therapies. Anumber of novel drugs, mentioned in this review, offermore specific treatments targeting either prostate cancercell surface proteins (CV9103, MLN2704 and 177Lu-J591)or introducing irradiated tumour cells (GVAX and IL-2/IFNgtumour vaccine) which may lead to activation of the hostimmune system. The obvious benefits of targeted thera-peutics would be the potential for minimization of adverseeffects and hence better quality of life for patients.Although cancer treatment vaccines may be beneficial forprostate cancer patients, cancer preventive vaccines areyet to be developed.

Anti-angiogenic treatments are one of the mostpursued areas in cancer treatments, regulatory approvaloccurring with bevacizumab (breast cancer, glioblastoma,renal cell carcinoma and colorectal cancer), imatinib mesy-late (chronic myelogenous leukaemia and metastatic gas-trointestinal stromal cancer) and sunitinib mesylate(stomach cancer and gastrointestinal stromal cancer). Inprostate cancer,a trial of bevacizumab as second-line treat-ment to docetaxel although showing good PSA responseswith overall PSA concentrations declining by up to 65%(7/20 patients had major PSA response, which includedfour patients who were prior non-responders to doc-etaxel), a contribution by bevacizumab could not be con-firmed due to the non-randomized nature of this trial[146].The results of randomized control trials with patientsreceiving either docetaxel-based treatment or hormonetherapy with and without bevacizumab are not yet fullyavailable or the trials are ongoing [147, 148]. Trials of ima-tinib mesylate did not yield good responses in prostatecancer and a trial was terminated due to severe toxicitiesafter single-drug treatments [118]. Despite these trialresults, there are a number of ongoing clinical trials com-bining imatinib mesylate and docetaxel-based therapies[121–123]. VEGF may correlate with the development ofprostate cancer but HIF-1a, a main regulator of VEGF, doesnot. Also androgen deprivation may also diminish VEGFexpression and thus it would be irrelevant to target VEGF inhormone-refractory prostate cancer patients. Similarly,PDGFR and PDGF are expressed in PIN, primary and meta-static prostate cancer but do not correlate with the prog-nosis of the disease. In the case of biomarkers which mayassociate with the development of disease (VEGF, VEGFR),targeting these biomarkers prior to subjecting prostate

cancer to any treatment (which several early phase trialsare currently undertaking) or prior to evident metastaticdisease may be more pertinent as a preventive approach[128, 148–151].

Targeting mTOR does appear to be a more promisingapproach as there is consistent in vitro evidence of expres-sion of mTOR pathway proteins leading to activation ofmTOR signalling, which correlates with the aggressivenessof prostate cancer. Pre-clinical data and a pilot study werealso encouraging where treatments of single agent mTORinhibitors initiated anti-tumour responses. Several trials oftemrolimus and everolimus are now ongoing and arebeing tested in a neoadjuvant setting prior to prostatec-tomy or hormone therapy [143, 152, 153]. These drugs arealso used in combination with bevacizumab in patientswith advanced cancer, which may allow targeting of differ-ent sub-populations of cancer cells in castrate-resistancepatients with metastases.

New generations of drugs targeting prostate cancerbiomarkers are novel approaches aiming at differentpopulations of prostate cancer cells that may be resistantor become resistant to traditional therapies. The majorityof clinical trials concentrated on finding new agents fortreatment of advanced disease in which treatments arecurrently limited to taxane-based chemotherapy. However,some agents can be applied as preventive treatments andare now being tested in a neoadjuvant setting. From thisreview, we can appreciate how finding potential biomark-ers and understanding their role in cancer developmentalprocesses can lead to promising new treatment targets forprostate cancer.

Conclusions

In prostate cancer, the main treatments are radical pros-tatectomy, radiotherapy and systemic therapies (hormone-deprivation therapy and chemotherapy). Prostate cancer isknown to be a chronic disease and better detection allow-ing long-term management will improve quality of life ofpatients.With increasing awareness of the existence of dif-ferent phenotypes of prostate cancer cell populations, per-sonalized therapy is going to be the future of cancertreatment. By taking advantage of our increasing knowl-edge of prostate cancer initiation, progression and biom-arkers associated with progression of disease, optimalregimens of novel therapeutic agents are now beingtested in early clinical trials and will hopefully pave the waytoward more targeted and individualized therapy for pros-tate cancer.

Competing Interests

There are no competing interests to declare.



Sujitra Detchokul was a recipient of a Medical & ScientificKidney & Urology related Research Biomedical ResearchScholarship from Kidney Health Australia and a University ofMelbourne Fee Remission Scholarship from The University ofMelbourne. This work was supported by the Austin HospitalMedical Research Foundation and the Sir Edward DunlopMedical Research Foundation.

Abbreviations and acronyms

177Lu = radionuclide lutetium-177Ab = antibodyADT = androgen deprivation therapyAg(s) = antigen(s)Akt/PKB = protein kinase BAR = androgen receptorBcl-2 = apoptosis regulator proteinCTL = cytotoxic T lymphocyteDC = dendritic cellDLT = dose-limiting toxicityDM1 = maytansinoidEp-2H = Ep-CAM-derived peptides Ep-2HEpCAM = epithelial cell adhesion moleculeGF(s) = growth factor(s)GLUT1 = Glucose Transporter 1GM-CSF _ granulocyte-macrophage colonystimulating factorHDACs = histone deacetylasesHIF-1a = hypoxia-inducible factor-1 alphaIFN-g = interferon gammaIL-2 = interleukin 2IL-12 = interleukin 12MTD = maximum tolerated dosemTOR = mammalian target of rapamycinN/A = data not availablePBMC = peripheral blood mononuclear cellPCa = prostate cancerPDGF = platelet derived growth factorPDGFR = platelet derived growth factor receptorPI3K = phosphoinositide 3 kinasePRAME = preferentially expressed antigen in melanomaPSA = prostate specific antigenPSA DT = prostate specific antigen doubling timePSCA = prostate stem cell antigenPSGR-1 = prostate specific G-protein coupled receptor-1PSMA = prostate specific membrane antigenPTEN = phosphatase and tensin homolog proteinPts = patientsRaf = proto-oncogene serine/threonine-protein kinaseRas = a protein superfamily of small GTPases.RT = radiation therapySAHA = suberoylanilide hydroxamic acidSTEAP = six-transmembrane epithelial antigen of the prostateTGF-a = transforming growth factor alphaTH = T helper cellTSC 1/2 = Tuberous sclerosis protein 1 and 2VEGF = vascular endothelial growth factorVEGFR = vascular endothelial growth factor receptor

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