The discovery and validation of new drug targets in cancer

632

The discovery and validation Sara A Courtneidge

and Greg D Plowman

Advances

in our understanding

pathways

involved in cellular growth control have provided

several new strategies

of the signal transduction

for cancer therapy. Recent advances

make it possible to develop

of new drug targets in cancer

selective

inhibitors targeting

now

genomic

instability, the growth, survival, and invasion of the tumor, and its nourishment

through the growth of new blood vessels.

and included oncogenes such as Kas, 3s ~vell 3s tumor suppressors such 3s p.53 and rctinoblastoma protein RI,. Iiccent studies have suggested, howu,er, that additional checkpoints function during mitosis to ensure propfx alignment and segregation of chromosomes, and so the deliwry of the correct complement of gcnctic material to each daughter cell. Recently. several oncogencs and

Addresses SUGEN Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA Correspondence: Sara Courtneidge; e-mail: [email protected]

tumor suppressors ha\ e been identified [S-7.8”,9.10”,1 1’*,12’]. including three seriiie/thrconinc kinases that function in 3 nornial cell during mitosis. Alteration of such genes may be responsible for the abnormal chromosome content (aneuploidy) and chromosomal

Current Opinion in Biotechnology

deletions prevalent in many cancers, particularly those of colorectal origin. Aneuploid! may Ix one mechanism I,\, which defecti\~e cells acquire an increased rate of muw

1998, 9:632-636

http://biomednet.com/elecref/0958166900900632 ~c Current Biology Ltd ISSN 0958-l 669 Abbreviations dIscoidIn domain receptor DDR IGFI insulin-like growth factor 1 IGFIR IGFI receptor integrin-linked klnase ILK PDK 3-phosphoinositlde-dependent PH pleckstrin homology Pl3-K phosphatidylmositol 3-kinase

tion, enabling them to adapt and cvol\x toward tumor progression. ‘I:,lrgcting enzymes in\.olvcd in the control of genetic stability and chromosome segregation may dcfinc 3 potential protean kinase

Introduction (kmcer

results

mishaps.

from the accumulation of ;1 series of genetic affect the control of cell prolifer-

Some mutations

cells \fith the ability to imn’e and sur\i\x at distant sites, or process necessary for tiinior growth. In recent pm, the rapid increase in the number of seqt~cnccd human genes, the combined use of genomics and arra);-based expression analysis, 3s uell as 9 deeper ation,

others

cndo\l,

tumor

from their normal location stimulate the angiogenic

understanding of many signal transduction pathways. has Icad to a dramatic expansion in the number of potentid cancer targets. ‘I’hc challenge is thus shifting from gene identification to rational selection and \ alidation of those disease-rclcunt targets that pro\idc the best opportunities for clevclopment of specifc therapeutics. b:e u ill cover some of these recent dtx~elopments in this raiew, Space limitations will not ~110~ us to cover the entire field of canccr therapeutics; therefore, IVC ha\,c chosen not to discuss strategies for replacement of tumor suppressor function. and p-e\ ention of drug inipiwwl immune sunxillancc, resistance. \Vc also refer readers to other more comprehensi\x reviews on angiogenesis [l-l]. Instead wc nilI focus on the application of target-driven drug discovery to new cancer targets that impinge on other aspects of tumor biology

Genome instability X common mechanism

potential

by u hich cancer cells obtain a gro\vth ad\witagc is through deregulation of cell-cycle checkpoints. ITntil recently, those that control the (; 1 phase of the ccl1 cycle were the most well understood.

‘Ike

new strategy

serine/thrconinc

for cancer kinasc

I’lkl

therap). is a mammali~~n

home-

logue of IAv.cop/I/IINpolo. \vhose cxprcssion is rcstrictcd to ccntrosonies and the niidzone of niitotic cells. In ?ho/m~, I’lkl appears to stimulate the activity of the phosph;ltasc cdc25, which is a kc); acti\3tor of (klc.! kinasc. I3ccausc ;I cell’s entry into mitosis is dcpendcnt on the :icti\,it! of (Xc? kinasc, I’lkl indircctlv rcgulatcs this cell-cycle transition through acti\xtion of bit cdc2.S phosphatse 1.51.I’llcl is frequently o\ucqxcssed in primary human lung tumors

and enforced o~xrexprcssion in rodent fibrol,lasts fii\.cs rise to ;I transformed phenotype [b]. IXsruption of l’lkl function

b) microinjection

of a neutralizing

antibody

into

normal diploid filxoblasts resulted in I?;rowth :irrat in (;2 [7]. \\Iien I’lkl function ~vas inhibited in a tumor cell lint. howc\w, no arrest \jx+ obscrlui. Instead the cells had alxxmiial ccntrosomcx and mitotic spindles. and \vcrc antuploid and multinucleatc [7]. ‘Ilie diffcrencc in beha\.ioiof normal and tumor cells when l’lkl acti\,itv w;is :ilxited. together with the owxsprasion observed in tumors, sug;gcsts that a 1’11~1inhibitor might hu\e clinical utility. A new family of nianimalian mitotic scrincithrconinc kinascs bvas dcscribcd recently, and nanicd aurora1 and aurora2 [X”]. ‘I’hey are the orthologues of /)/~o.co/~/II/~ aurora, \vhich plays a role in chromosome segregation in flies. ‘I’hr human aurora2 protein is localized to ccntrosomtx and the mitotic spindle apparatus of di\,iding cells. but is rapidI>, Jo\vnregulatcd prior to anapliasc. Not only is aurora2 o~ercxpresscd in most human tumor cell lines, and in many primary tumor\, but chron~osonial localiution studies sho\ved that it lies on the 2Ocjl.i amplicon and is amplified, o\~ercxpressed, and 3cti\3ted in >508 of primary colon caners and 10% of priniar) breast cancers [X”]. O\,crexprcssion of aurora2 results in

The discovery and validation of new drug targets in cancer Courtneidge and Plowman

the trtinsformation

of Rat1 fibroblasts,

suggesting

that

it

can ha1.e an impact on kc): regulatory pathways. In addition, prctiminary target validation stnciies suggest that abation of aurora2 leads to grow:th arrest of tumor cells ((;I) Plowman, J Rischoff, unpublished data). ‘I’hese featllres make aurora2 tin attractive target for developing enzymatic inhibitors for cancer therapy. Yet another

interesting

the mammalian Rubl. In yeast, properly ulates

mitotic serine/thrconine of S~~h~rof~y~s

orthologuc Bubl appears

to fiinction

kinase is Bubl, mwiL.Isim

as 3 sensor

subsequent apoptotic cell death [ lO”]. ‘I’hese findings support ;I conserved role for Bubl in yeast and mammals 9s an important regulator of 21 mitotic spindle assembly checkpoint. Hub1 has been proposed to be a target for mutational inacti\Wion in some colon tlimors. specifically those displa)ring chromosomal instability [l l**]. ‘I‘he authors propose that these mutations Icad to loss of the spindle assembly checkpoint and aneLlploidy. Further target \,alidation stlldies \vill have to be undertaken in human cells to more clearly- define

the role of Rubl.

‘l’hc finding that several mitotic serine/threoninc kinases are inappropriately reg&ted in human t\lmor cells. and art: associuteci with chromosomal instability sllggcsts that ancuploidp may be causall?; in\~olved in tLiniorigenesis. Based on these findings, new therapeutic intcr\,entions art: suggested, including the de\~ttlopment of small molecule inhibitors of the mitotic kineses anrora2 or Plkl. In addition. it may be possible to exploit the differences in mitotic checkpoints bet\vccn normal and tumor cells to improve the selectivity of currently available chemotherapy.

Cell survival, extension inhibition of apoptosis

of lifespan and

Prolonged cell snr\i\al can provide ;1 growth ad\2ntage to tumor cells e\.en in the absence of accelerated proliferation. Sc\~~al nc\l. contriblltions in this field havt: been made recently including insulin-like growth (&~cit~~MS.s

the roles of factor 1 (I(;l:l)

P/~~N.Ydeath

Akt is a mammalian

genes,

proto-oncogene

t\\.o kinases, Akt, the receptor (I(;I:lR), nev and telomerasc. related

of a direct

interaction

homology

of phosphoinositides

(PH) domain

of Akt, localizing

with Akt

to the cell membrane [l-l’]. and allowing access to 3-phosphoinositide-dependent protein kinase (PDK) 1, which activates Akt by phosphorylation at ‘I’hr3OH [ 1.5”.16”]. Full activation of Akt, ho\vever, requires concomitant phosphor);lation of Ser473, suggesting an additional upstream kinase (PDKZ) may also be reclnired.
and

for

aligned chromosomes during metaphase, and rcgthe mitotic checkpoint prior to initiation of

arqhase [9,10”.1 1”,12’]. Disruption of mllrine Bubl hvith a dominant negative reagent results in premature exit from mitosis in the presence of a damaged spindle and

ttlmor

the result

the pleckstrin

633

to the retrovi-

rat oncogcne V-N& and encodes 3 serine/threonine kinase. Recent progress has ad\2nced onr imderstanding of hoI+ Akt is rcg<ed by ~~hosphatid~linositol .i-kinase (PI5K) and has led to the identification of several of its Llpstream and downstream signaling partners. ‘I’hese data point to acti\,r\ted Xkt LISa key survival signal protecting cells from apoptosis. and sugjiest that its dcregnlation would pro\idc a growth advantage to tlinior cells. It has been recognized for se~wal years that PIA-K activity is required for gro\vthfactor-mediated acti\.ation of Akt [ 1.11. ‘I’his regtllation is

\Yhat art: the cio\vnstream signals initiated by Akt that result in cell snrvi\A? Studies in hematopoietic. ncuronal, and epithelial cells do not support the involvement of the 1\IAPK pathway, p7OS(,K or the G’I’Pase RX in Alit signaling.

A possible

connection

lvith

the

Hcl-2

family

of

apoptosis-regulating proteins has recently been suggested as the Rcl-2 protein BAD was found to be ;1 potential target of Akt phosphor\lation [ 18.191. \\:hereas Rcl-2 homodimers promote cell survival, hcterodimerization with BAD promotes cell death. Akt phosphorylation of HAD facilitates its binding to the 14.14 adaptor protein. preventing heterodimerization with Hcl-2 and thus reversing the cell death signal reglllated by BAD. Intriguing as this is, however, HAD has ;1 very restricted expression proflle, and this pathway dots not appear to bc reclnircd for many of the snrrival functions attributed to Akt [?(I]. Nevertheless, the obsrrlation that a related kinasc, Alit& is amplified and overexprcssed in a subset of pancreatic. ovarian. and breast carcinomas (many of \vhich express ;m activating Ras mutation) [21,22], suggests that ;m inhibitor of Akt or AktZ might be of therapeutic benefit. In addition, these data warrant a closer insptzction of the expression, regulation of the Llpstrcam kinases Pl)Kl and PDK2.

and activity

Implication of IGFl R signaling in tllmor progression is based in part on the pleiotropic a&it& of its ligand IGFl. and o\erexpression of the receptor in solid tumors [23]. ‘I’his signal plays an important role in mitogenesis, cell survl\al, motlllt); and adhesion. ‘I’hese diverse activities ha\-e prompted studies of its efficacy for treating diseases including osteoporosis, grolvth cicficiency. catabolic disorders, diabetes, and neurodcgenerative diseases, such as amyotrophic lateral-sclerosis. ITnderstanding the role of l(;Fl R in ccl1 survival is an arca of active research, although relati\zly few insights have been made in recent years [Z-l]. ‘I‘his year, ho\+,ever, a retrospective stud) reported that men with high strum levels of l(;Fl were four-fold more likely to dcvclop prosratc cancer than men exprtzssing L-i-fold less I(;I;l [25’]. ‘l’his provocative carrelation supports an association between IGFl signaling and tllnior progression, and encourages further efforts on targeting new therllpies at this pathnay Additional analysis of of the first Lvith the

cell survival targets are likely to come from invertebrate genomes. ‘I’he genetic composition metazoan organism will be available in late 1998, complete scclnencing of the 100 megabase

634

Pharmaceutical biotechnology

~cnomc

of 6’. &U//S. As -70% of dI in wornis. and are often

liolnologues

chanjieablc

with

the worni

,gcnctics to implicate in apoptotic

genes

hxY2

functionall~~

(~‘l’l’mx

inter-

one can tisc \fwrni

cotintcrpart,

human gcncs that are suspectccl to lit

signaling

from the cloning

humall

:\ recent csaniple

pathlvuys.

of the 6’. dqy~m cd-.5

tion

;~ffecrs ccl1 death [26”]. human SI 1.3~tloinain containing

,grnc.

conies

whose

liiuta-

(k-5 pl-otein is related to a protein IX)(:KlXO [27] and

;I /~~uco~h?l/i/~~protein niyoblast city [2X]. (Lx-.5 is the first to scqucliccd from ;I list ofat lcxt six wmii genes inwhd in the cn,g~ilfmcnt of dying cells. ‘I’hese genes arc iniplicatIx

cd in the cytoskcletal sprd

cn,ylf

mid

rcorganimtion

cell corpses.

for cells to of the signaling

rcqtiired

I>isscction

pthua!s utilized b! ccd-5 k\ ill prohbly enhance our iindcrstanding ofccll death in htinixis 2nd possil~l~ pro\ idc additional cell siir\i\.al targets u ith rcle\ ancc to c;incc’r.

c&42

sion

a

of

normal

l-S;\-depcmdcnt tclonicxs

all’s

I>N.A

~iioso~iics

on human niincd

function

tclonicrc

length.

acti\,ity is obscrbcd

(I\ hich do not norni;dly step

in

the

tcstcd.

It has Ixcn

uprqgiilatctl

in

tclonicrasc

Studies

tcIoiiicmsc

in

in soimitic

such h~pKhcscs

tancc for the control

that telonicrase and that

cells,

in a prolonged

factor

rcceptor

platclct-deri\.cd

estd)lishecl

pm\ th or s~ii-~~iul of the tumor.

can

Nc\xrthclcss.

that telonicrase

will

is

rcccptor

of

inhibit

the a\xil3l)lc

lx an :ittrxti\c

c;iii-

Tumor environment ondary

sites

invasion,

adhesion. migration, Studies on the niolccular

Kcncsis.

primarily

focusccl

protciscs:

on

three

nictastasis

cr~lcs. in-depth

As

targas,

11c will

sion

in\-ol\,cs

from

sc\.cral analysts

in tumor

;I primary

di\ crsc

his

general

and

angio-

of metastasis ha\x classes

;iiid

rcccnt re\ ic\vs of mctalloprotcasc clisciiss

to sec-

includin,q

proccsscs.

pi-oliferation,

suppI-cssors:

briefly

ttinior

of molecules:

adhesion

[Z-4] and

ha\c

molcgi\,cn

angiogencsis

here only the role of adhc-

altcrnati\.c

straw@

for

intcr\~cntion.

of

pathu2ys. I:or

these

pro-

suggesting

ewiiiplc,

is the discoidin

‘I’his

tissue.

cloned

rcccptor was originally

cells.

Iktailcd in Ix-east tumors

2nd

role

;I

in tiinior

play

211

doni~iin

from

an;llysis

rwcalcd

\\.hcii

compu3.l I\ 3s swig-

in\ ;i5ion

gestcd [X,X]. licccntly, the extracellul~iim;\tris protein collagen was identified 21s;i ligand for I)I>K [.~7”..iX”..iO~. (hllagcn also binds the cd/31 alxi alp1 intcgrins Icadiiig to sipials that control ccl1 migration and pi-olifcration. ‘I’his

potential

link

possibly the

betuccn

\\ith

tumor

complexity

or tumors. .A better

tissues,

ronmcnt. of cclliilar

and

intcgrin signaling is intriguin,g. ;incI ‘I‘hcsc cuniplcs high-

I)I>K

niet:isusi5 fui-thcr.

of cellular

intcrxTion5

that

allo\\

to rccei\ c CIICS from their Ioc;iI cn\.iIindci-standinfi of the molecular n;it~irc

comm~inication

for blocking (Iadhcrin

tumor

inay

pro\ idc zriditional

targets

g:ro\f th.

2nd [3-catcnin

niutatcd

in cancers,

CCIIS. (:adhcrin

2nd

phorylation

the

do\\~nrc~.“latcd OI-

arc frcqiientl!-

and arc txlic\

cd to play an important

role in the dccrcaseci cell adhesion of tlinior

and nictasutic

dc,yxd:ltion

the intixccllular

to its sulxtrates.

potential

Icads to tyro\inc

signaling

of

pool of B-catcnin

Hhl(;

including

pho\-

thcrcl)\

Ij-c;1tciiiii,

a\ kiilablc foi

Im\; tl-anscription

factors and the :idcmoni;~tou~ polvposis coli (-\I’(:) tuiiioi suppressor protein. ‘l’hrough thcsc iiitcractioiis. p-catcnin i-cgulatcs gcnc expression. cell niigi-ation. and ccl1 atlhcsion.

~\dclitiond

upstrcani

pl) cogcn s) nthac [-IO]. An

CIi;ii-;iCtCri%;itioii

studies pcutic

3Iso

domains. niatri\-

and

product

to the intcgrin-cacl-

controlling

C;l/S

results

O\ crcxpi-ession

II,K

intcr\.cntion.

tlccrwscs

I I ,k:

b-cad-

Ox-crc\prc\\ion

cell tr3ilsforiii;itioii.

in nude

2s another altho(lgh

of

of the c\.cIin-( Xk

pi-ogrcssion.

if it is o\uc\prcsscd

:I

;inchoragc-iiidcllcndcnt

actiwtion

in cpithclial ~1s tuniors

(ll,h;).

I;in;lsc

to the beta1 2nd Ixt:l.?

assciml)l>;

intluccs \\ith

I)?- grou tli

dctcrniinc

that binds

pro,g:“ssion

support

addition

include

01ico~:cnc

integrin-linl
fibroncctin

cxprcssion,

complescs

slired

of

kinasc

cytop’l:isniic

cell-c!clc of Il,K

recent

of (j-atciiin

kind u ntl

si,cn;il transd~~ction p;lt11\\~:1!~ h;I\ coImc flroln

scrinc/thrconiiie intcgrin

repilatoi-s

kin;isc-3

intcrcsting

herin nicdiatcd

hcrin

xqccts of nictxmsis niolccules. such as their ligancls. \\liilc g thcsc cxtr;iccllular many

that ina)

kinasc

that it is 0~ ercspressed

cnhanccs

progression.

\lan! of the atihcskc and migration arc attril,utcd to cell-sllrtke adhesion and cadhcrins. selcctins, intcpins. much effort has focused on blochin interactions. it is no\\. rccogiixd thlit teins use similar intrxellular sigiuling

[N].

inwsion

c3rcinoiii;i

and

is acti\-atcd

tvrosine

to normal

binding of cancer cells

factor receptor signaling

receptor

(I>I>K).

dccrcasing

didatc for drug dc\-clopmcnt.

‘I’hc sprc;ld

cd gro\\xh

cC\‘Ki co-;woci;itc.

role in tunior

breast

imporjiro\\di of

the platclct-dcri\

intcgrin

ligand \itronectin

One intriguing

through

of

inhil,ition

tumor

groudi

b) the intcgrin

important

the

light

[.iO’]. I~ormal tar-

rcquii-ccl to test \\hethcr

and

descr\~cs to he csplorui

mxxcxpression

lifespan

[.X3]. I:or cxainplc.

twmor cells

sug-

tr:rnwription

II to iii ;I

gel

of ~iiichorag~-indcpendcnt

ccllc

to Ix

hn\

cellular matrix interactions can also affect si,gnalin:: grou th factor receptors. \\.hich may he of particular

2nd

telomci-xc

of human tumors. cnxvmc

has allo\\ui

an alrcatly

suggests

is dcter-

tclonicraw acti\,ity) is a major of htiiiim cancers. ‘I’hc rcwnt

shoum

jict \~alidation \\,ill Ix

the

ha\~

tumor

results

I~tirthcrinorc,

of this

progression

of tcIonicx3sc

c\~idcncc

recombination.

in the majorit!

that rc;icti\,ation

cloning

an

to protect chroniosonics

inappropriate

and

synthesizes

cells in culture sliggcst that cell lifespan by

fcsting

that

is

tandem rcpcats) at the end ofchro-

‘Iklonicrcs

[29].

‘lklonierasc

polyiicrasc

(guaninc-i-id

from degradation

may bc through the cstcn-

lifespan.

Ixxn colI+y~i

I’l.~-Ii-dcpendcnt manner [.il’]. I~mhcrniorc, CW.i4 intcgrin acti\xion also increases cellular in\~asiwncs~. agin in ;I 1’1%K- and Kac-dcpendcnt ni;lnncr [AZ]. Intqrin and cuw

hunian A CICLXY 5ur\,i\;il tactic oftuniors

Kac ha\,e rccentl>and in\xi\cncss in

and

induce cell migration

niicc

possihlc

~1sinca

[41.-+2].

‘l’hc\C

target for thcra-

it \\ill first- Ix in an\ hilman

important tuniors.

to

The discovery

and validation

9.

Conclusion (:anccr

therapeutics

I’otential

oncology

screening

gcnc

p-cd

with

and

normal

\xlidation

(using

ti1.c alleles. targcts

prior

Se\~erd

nerv therapeutics

rationale

to

inhibitors exrension stantial rargets.

aspects

\\k

only include

anticipate c)-totoxics

rely on specific the tumor

has

drugs

doniinmt

used

to

the clinic,

In this

by such a and

rtxicn;

biology

and altered

adhesion), in defining

that future

cancer to combat

high-

insrabilit); who-c

sub-

molecular

therapies

and anti-prolifer3ti\es, designed

antispecific

we have

(gcnoniic

been

made

these screens.

including

will not aspects

Roberts BT, Farr KA, Hoyt MA: The Saccharomyces cerevisiae checkpoint gene BUBI encodes a novel protein kinase. MO/ Cell Biol 1994, 14:8282-8291.

Cahill DP, Lengauer C, Yu J, RiggIns GJ, Willson JK, Markowitz SD, Klnzler KW, VogelsteIn B: Mutations of mitotic checkpoint genes in human cancers. Nature 1998, 392:300-303. This paper and Taylor et al., 1997 [IO”] describe the sequence and function of mouse and human Bubl kmase. Yeast Bubl IS required for a delay In anaphase entry In response to spindle dIsruptIon. Slmllarly, the mammaltan counterparts localize to the klnetochore during mitosis, and expression of dominant negative mutants result in failure of cell-cycle arrest followlng spfndie damage. Cahill et al. suggest that Bubl IS involved in a spindle assembly checkpoint, and that a defective Bubl results In chromosomal instabIlIty, a common trait of colorectal tumor cell lines. This study also found 2 of 19 pnmary colorectal tumors to contain mutant Bubl alleles, and suggests that the resultant aneuploldy may play a role In tumor progression. 12.

PennIsi E: Cell division gatekeepers 279:477-470. ;\n excellent review of presentations at the Biology meeting describmg the molecular proper alignment of chromosomes prior to 13.

identified.

Science

1998,

1997 American Society for Cell basis of how a cell senses the entering anaphase.

Burgenng BM, Coffer PJ: Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature

1995,

376:599-602.

Franke TF, Kaplan DR, Cantley LC, Toker A: Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4bisphosphate. Science 1997, 275:665 668. This paper shows in “fro bIndIng o! the AKT pleckstrln homology (PH) domain to PIP,, Pl(3,4)P,, and Pl(3,4)P,. BIndIng of these llpids results in actlvatlon of the AKT kinase. 14. .

life cylc.

References and recommended

15. ..

reading

Papers of particular interest, published wlthin the annual period of review, have been highlighted as: of special Interest “of outstanding Interest

Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT: Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997, 277:567-570. See annotation to [I 6”l. 16. ..

l

1.

Folkman J: Angiogenesis in cancer, vascular, diseases. Nat n/led 1995, 1:27-31.

2.

Augustin

3.

635

Taylor SS, McKeon F: Kinetochore localization of murine Bubl is required for normal mitotic timing and checkpoint response to spindle damage. Cell 1997, 89:727-735. See annotation to [l l”].

of

Acknowledgements

Pharmacol

and Plowman

IO. ..

but \vill also these

Courtneldge

..

ncga-

prioritize

in cancer

11.

complex and target

inhibitors.

of tumor

of lifespn. progress

or sur\i\xl.

and

thar Lvere identified cnumxl

of angiogencsis. other

simple

high-throLlghput

rnetalloproteasc

prolifcrarives, lighred

are

target-bad

ha\xz already

by dissecting

characterization

knockouts)

b>

cells coni-

control

such as antisensc,

tools

~lge.

identified

counterparts. from

tiioleculsr

or gene

molecular

in tumor

such as growth

genonies

Iktailed

the routinely

expression

cellular

processes.

Iw coinparing

organisms.

entered are now

protein

and

their

the biological

h3s targets

of new drug targets

HG: Antiogenic tumour Sci 1998, 19:216-222.

therapy:

rheumatoid

will it work?

and other

Trends

Brown JM, Glaccla AJ: The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998, 58:1408-1416.

4.

Pluda JM: Tumor-associated implications, and therapeutic 24:203-218.

5.

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