DTIC ADA422345: Role of Androgen Receptor in Growth of Androgen Independent Prostate Cancer

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‘VKULM; Role ef Androgen Receptor in Growth of Androgen
Independent: Frosvate Canc:

PRINCIPAL INVESCIGATOR: cChavlie D. Chen, Px.D.

CONTRACTING ORGANIZATION; "he University of California,
Los Angeles
los Angeles, California 90024-1406

SPORT DATS: January 2004

TYPE OF REPORT: Annual Summary

PREPARED FOR: U.S. Army Medical Research and Mater‘el commend
Fort Detxick, waryland 21702-5012

A-SUPIBUTION STATEMENT: Approved for Public Release;
Dintzibction Unlimited

the views, opicions and/or fin@inga contaired in this repor: ere
those of the acthor(s) and should not be construed as an official
Eepartnent of the army positian, policy or decision unless ae
desigaated by ocher dacumertation.

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WHE AD SOT 5 FOND NERS
Role of Ardzogen Receptor in Grovth of andvoron Bae 7-02-1~-9034

Endaperdent Frotoare Cancer

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TE ARSTARCT Tis 200 Ware
Hormone sterapy ip an offactive tresteent for advanced tummy gestive DHS) prostare
Concer. fowevar, the treatnent ia short-lived and asrume refractory (BX) cancer
Guentuclly developa, “hrovsn gene Rrofilizy uaing seven palre of RG ecd ER wavografte, ‘we
{Sentisied overespracaton cf androgen zezeptor IAR) 1a the ony consistert chewgn in thy
progzessior of prosnte cancer. in the first grond perio€ 101/02-10/03), ve conriried chat
BR peotein ia elevaved =n FH cimors. Using lenciviras scé retroviruy sysloms, he Wave al
te overomuvese Ax dn ES prostave cencer cells. In vitzo and im vivo experimants
Henonetsated toat ovorenncesedon of AR fa aufGirient for EE-vo-IM teaneition. Ne ale>
Seveweped 2 system (shsiia) to Frockcnan AR 1s OR iaCae colle ané slican thal Ab-fewckdown
Sbotlshed AR paenatype de vitro, in che Lact grand period (C1/03-01/011, vo eomoastrated
Fear everexpceseion Of At iv required for hozmore refvectury proatace conser im vivo USiCg
both buece and INcaP cella, Althours, we were arable 2 obtain conciustve ses} n Lo
Aetermine thr cocheaiza fox AP overexpression, wo dnnangtreted that gene arplifieatien is
fot the ale cause of the qyerexumuaion

TR SURELY TER TE ER OF PAE
Ebostabe cancer, androgen recepzor, andzayer. andepandont 6
7 ICE CBE

STREEURTTY ASSOATION | Te SRCUIOTY CLASSIIGRTION —¥8, ECORI ELAESRICA TON —| Zl TATION OF ABSTRACT
rolassiised Unt ted unlimited

TENT HT - Eowwaan
Table of Contents

COVE a

SF 798,

‘Table of Contonts..

Introduction.

Bow

Key Research Accomplishments

Roportable Outcomes.

Conclusions.

Raferences,

Appendices.
INTRODUCTION

Tproposed in the grant :0 enamine if averexpression oF androgen receptor is necessary and
suffcient for prostate cones progression from androyon dependen! i independence: Hors the
terms are changed to hormone sensitive to kermtoue reftecton), In the frst grant pet‘od, I
<demonshated chat overoxpression of and-ogcr. receptor is suffcieut forthe progression in vite
and in vivo, In his gran petiod, { desuonstrated that overexpression of androgen receptor is
necessary Tor the progression.

BODY

Nevesnigy et
‘To knockdown AR in TTR APC: cells by RNA inlerference

Tr the frat grr pried, we demonstrate that AR is required lor grown of HR NCEP calls
ning SHRI. Ta determine thot the phensrmenun tnt specific ly HR LNCAP cela, we ala
Iknockad down AR in LAPCGS, another TR cell lie, using the some tevinology. When cells were
inmpanied into the Mans oF-castrated male mice, hoth knockdova cells (LNCEP and LAPC3)
grew slawiee Gian vector-infected controls (Fignre (). Moreover, those tumors that did grav did
‘ot express GTP when eompared to wectoe-infected controls (jets) and still expressed AR.
protein (data not shown), inciting selection fr eells that eseaped AR knaclalnwe. These dasa
indiease that increased AR Jovots ate necessary for bormone reftactory proslate cancer,

o
o

“i ae

Tumor volume frm?

‘Tumor vatume fom)

* Timea” Time ea) “*

gare |. Anaiogan rorqpr express is aonssary fa hoamone scasitveanhor eens refractory
ragronsion (a) Scho-aatic of kN letviras ered ating: androgon reoptor (b) Taror calves it
SLM) otheraone refustory LAPC ells infected with ether se stN A-ccmeaing (bus, 2 =) a2
ante vu (rey n= 99 sivas = 0.05, es). Kight inset west luk ul shRNA expressing uml
consol (omy v2cion calls, Lat isc, faw oviomets Zor GF>-aekive cells oF mpvesematise turats
euntul vins op: ang reeepior SHRNA vu, bolls. (€)Tusnoe volo (4% SFM) faa sir
‘expense esing hormone atacrory LNCaP calls

‘Mechanisms of AB ovsrexprossion, Inthe ovig"nal proposal, ee proposed to study the
‘mechanisms responsible forthe ovevexprcesion of AR in AT Lumors. Up to:novs we a unable 70
generate data forthe atisinal proposed work, becauso we coal not gat enough muniber of sing.c
celle for euch pair of nenogmats, We have alfcady tried this esperimenis Cee tives. We are
optimizing the digestion pretoca! 10 improve the yield,

Iwas demonstrated tat hormesae rectory prostate cancer samples have AR gene amplification
(Visakorpi etal, 1995) To examine ifthe gone amaplifioasion can explain our xenograft Ainding,
\we initiated eallaboration withthe Visakorpi groap ‘n Finland. We performed the comparative
genome hybridization (CGH) on hormouo sensitive rod borane reffaclory puirs oI LAPCA, 8,
sand ENCUP. Tsing this method, we did not abserve any AR gene amplifcatiem in hanmane
reffuctory xenografis compared us “heie respective hormone scustive coumterparts, auggesting
that gon amplification earno be the sole cause i ata, Poe tac overexpression,

Table 1. Compatstive gonomie lybriization (CGT) m hormone sensitiv
relacity (AR) LAPCS and 9, sad bormous sensitive LNCP.

IS) aed hormous

Sampa Gains Losses
D13e924, 3924 per, ean-c22,
ois Tpte-per, ap2icper, ater
P1321, iT ple, Buen-e22
pak Tp14 pe, pt per, 17924-hor
1p82per, 2424, 94, 160,
fo ‘Trager, 19,22, XyZt-aes
paper, 2924, 924, 109, “p22 31, 2e22 qed. plete, Sotd-ater,
sR Taps, 19, 22, eRO-qe8— Gear-gPd, ge2t-g2’. 1aq2"-cier
LvcapHs 13 RptS-92, 4426-6392, Boone, 18q21-<25
LNaP HR not dane ra dae

KBY RESKARCH ACCOMPLISHME)

7

Demonsiratet that AR overexpression is necessary for hormone rettatory arostars eamce
ByRNA Inaelslowr lechnolagy
2, Demensirated that AR gene orplication is not the sole canse ofthe overexpression
REPORIABLE OULCOMES
Nene

CONCLUSION

Th the Wt grin prin, T was able tn demonstrate sha. AR everexpression is necessary for
hormone reffactory prontule cunear pragresion in vito, We alsa demonstated thst gene
amplification ig nthe sale cause athe AR overexpression

REFRENCES

‘Visskoopi,, Hywinen,B., Koiesto,. Taupe, M, Keiunen,R, Pale, ©, Pulte & Lamina Il by
0d Kallioisn, OP. (1998). vive assent te arurcgen recep gern peegsnion na
reste omer at Genet 0-26.