Oncogenomics to Targetthe Tumor Cell in its

Microenvironment

Kenneth C. Anderson, M.D.

Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute

Harvard Medical School

Tumor-Promoting Influence of theMicroenvironment

Growth andsurvival factors

Cytokines andchemotacticfactors ECM

Proteases

- Growth factors promotetumor cell proliferation andsurvival

- Cytokines and chemotacticfactors promote tumor cellmigration and invasion

- Proteases break downbasement membrane, alterarchitecture of tissuestructures, and promotemigration/invasion of tumorcells

Modified from http://www.the-scientist.com/images/yr2003/sep08/tumor.gif

VEGF

Intratumoralangiogenesis

Peritumoralangiogenesis

Blood vessel

• Tumor endothelial cells areuniquely altered in differenttumors

• Tumors produce factors(VEGF, FGF) that recruitendothelial cells

• An anti-angiogenesis drugthat targets VEGF is FDAapproved (Avastin)

Tumor Vasculature-Blood Vessels

Tumor

Normal MGUS Myeloma

Gene-Expression Profiles AssociatedWith Progression to Myeloma

Davies et al. Blood 2003; 102:4504.

Molecular Pathogenesis ofMyeloma

CELLPROLIFERATION

N MGUS MM PCL

52 GENES

Survival – TNFSF7

Signalling – MD2, MACS

Structural – ADD1, VCL

172 GENES

Membrane – CD38, CD27

Tumour Supressor – RB, ARMET

Transcription – XBP-1, ZFP

Death – TAX1BP1, TXNL

UP

RE

GU

LA

TE

DD

OW

NR

EG

UL

AT

ED

ADHESION

DNAREPAIR

91 GENES

Oncogenes – BCL2, LAF4

Transcription – FOXG1A, RING1

Development – SHH, WNT

22 GENES

Transcription – RING1

Development - FRZB

Davies et al. Blood 2003; 102:4504.

Oncogenomics to Identify Targeted Therapies

Functional validation of MM candidate genes.

Integrated platform Integrated platform aCGHaCGH, SKY and expression profiling, SKY and expression profiling

55 MM Cell Lines; 73 Patient Samples

Anderson and Depinho

Expressed Genes: 258

Small molecule Monoclonal Abs

% r

ecu

rren

ce%

rec

urr

ence

6060

6060

40402020

40402020

00

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1515 1717 1919 2121 XXChrChr..

46 amplicons - 658 NCBI genes

FGFR3

MMSET

C-MAF

ITGB7

CCND3

CCND1

CCND2

Proliferation

Hyperdiploid

PB PC 4p16 maf6p21

11q13 D1 D1+D2NONE

D2 HMCL

Classification Based UponExpression Profiling

Bergsagel et al. Blood 2005

TC Classification

Transformation

Differ

entia

tion

Anti-apoptosis

Un

limited

Pro

liferative P

oten

tial

FGFR3D 13

Mcl-1, Dad-1

FLIP

Xbp-1

Telo

merase

Ubiquitin/

proteasome

Stress R

esponse

Angiopoetin-1/IL8

Transcrip

tional

Activity

Telo

merase In

hib

itors

An

tisense, T

elom

estatin

FGFR3 Inhibitor

Mcl-1 antisense

Hsp70/90

Geldanam

ycin

Riboso

mal

prote

ins

Angiogenesis

CDC34

Anti-angiogenic Agents Proteasome

Inhibitor – PS-341

Individualized Targeted Therapy

Genes modulated in MM

Function of gene products

Targeted therapies

Munshi et al. Blood 2004; 103:1799

BM

stromal cells

GrowthSurvival Drug resistance

Cytokines

Adhesion molecules

MM

Gene Modulations Triggered by Binding of MM Cells to BMSCs

before after 12 days

Days from cells injection

sIL

-6R

(pg

/ml)

20 30 40 50 600

1

2

3

4

5

6

7B-B4-DM1(150 mg/Kg)

In Vivo Model of Human MM in Human BM Milieu

Bone chip

Human bone chip

Tassone P et al. Blood 2005

MM cellMM cell

BMSCsBMSCs

ApoptosisApoptosisregulationregulation

Transcription/Transcription/translationtranslation

controlcontrol

OncogenesOncogenes

Heat shockHeat shockproteinsproteins

ProteasomeProteasomepathwaypathway

pimpim-1, -1, pimpim-2-2

__ Hsp90, hsp70Hsp90, hsp70

__ 26S 26S proteasomeproteasome subunits subunits__ ubiquitinubiquitin B, B, UCEsUCEs__ USPsUSPs

__ XBP-1, c- XBP-1, c-mafmaf, TCF8, , TCF8, relrel-B-B__ eIFeIF-2, -3, -4, HDAC1-2, -3, -4, HDAC1

__ FLIP, FLIP, survivinsurvivin, , cIAPcIAP-2, -2, MclMcl-1-1

CytokinesCytokinesChemokinesChemokines

CytokinesCytokines

MicroenvironmentalMicroenvironmentalinteractionsinteractions

TranscriptionTranscriptioncontrolcontrol

ProteasomeProteasomepathwaypathway

__ HDAC2 HDAC2

__ 26S subunits 26S subunits__6, 6, __4, 4, ATPaseATPase 3, 3,non-non-ATPases ATPases 3, -4, -73, -4, -7

__ IL-6, IL-1 IL-6, IL-1__, HGF, IL-8,, HGF, IL-8,__ IGF-1,Gas6, MIP2IGF-1,Gas6, MIP2__, -2, -2__,,__ CXCL-1, -5, -6, -10, -13CXCL-1, -5, -6, -10, -13__ DKK-1, DKK-1, __ WntWnt-5a, SHH-5a, SHH

__ IL-6, VEGF IL-6, VEGF__ IGF-1, LIF IGF-1, LIF

__ integrinintegrin __55__ fibrillinfibrillin 1 1__ collagen V collagen V__11

MM cellsMM cells

MM cells

Bone MarrowStromal Cells

PBMC

IL-6

TNFa

IL-1bA.Thalidomide /IMiD

IL-2

IFN g

CD8+ T Cells

C. Thalidomide/IMiD

E. Thalidomide /IMiD

Bone MarrowVessels

ICAM-1

VEGF

bFGF

D. Thalidomide /IMiD

B.Thalidomide /IMiD

NK Cells

Thal/IMiDs Target MM Cells in theBM Microenvironment

Hideshima et al. Blood; 96: 2943, 2000Davies et al. Blood; 98: 210, 2001Gupta et al. Leukemia 2001; 15: 1950

Mitsiades et al. Blood 2002; 99: 4525Lentzsch et al.Cancer Res 2002; 62: 2300

VEGF

IL-6

IL-2

Bone Marrow Stromal Cell

Dendritic Cell

PKCz

NFAT

PI3K

IL-2

T Cell NK Cell

MM CellIMiDs

Mechanisms Whereby IMiDs Augment Anti-MM Immunity

Apoptotic

MM Cell

CD28

LeBlanc R et al. Blood 2004; Hayashi T et al. Brit J Hematol, 2005

• Preclinical (2000): targets tumor (caspase-8mediated apoptosis) and microenvironment in vitroand in vivo in animal model

• Phase I trial (2001): MTD; favorable toxicity; stabledisease or response in 79% patients

• Phase II trials (2002-3): 80% stable disease orresponse

• Two Phase III trials (2003-4): Revlimid/Dex versusDex/placebo in relapsed myeloma

Bench to Bedside Development Of RevlimidTargeting MM Cell in its Microenvironment

Time to Progression (months)

Pro

po

rtio

n o

f P

atie

nts

2.5 5 7.5 10 12.5 15 17.5 20 22.50

0.2

0.4

0.6

0.8

1.0

Phase III Trials

Len/DexDex

P < .000001

009

009

010

010

Len/Dex DexCR (%) 20.2 4.0

CR+PR (%) 60.3 22.2

Bortezomib: From Bench to Bedside

1994 NF-kB is a therapeutic target in myeloma1995-7 Drug discovered (Julian Adams), NCI 60 cell line1998 Phase I trials started2000 Phase I trials: safe and has anti-MM activity2000 Targets MM cell and BM microenvironment to overcome drug resistance in laboratory and animal studies2001 Phase II trial: 35% responses(including CRs), duration 12 months, with associated clinical benefit shows remarkable responses in patients with advanced disease unresponsive to known therapies

2003 Accelerated approval for relapsed refractory disease by FDA

2003 Phase III trial fully accrued and stopped early due to delay in TTP in Bortezomib cohort

2005 FDA approval extended to relapsed myeloma

2004 Phase II trials upfront and in combination

Bortezomib: From Bench to Bedside

Combination of Bortezomib + Revlimid

0

20

40

60

80

100

0 10 20

Bortezomib (nM)

% c

ontr

ol

0 uM5 uM

Revlimid

0

10

20

30

40

50

IMID

3 (7

2 h)

PS341

3 nM

IMID

3 (7

2 h)+

PS341

% c

ell d

eath

Patient Cells

SchemaLenalidomide, mg

Cohort 8Cohort 6Cohort 4Cohort 21.3Cohort 7Cohort 5Cohort 3Cohort 11.0

2015105

21-day cycle*

1 4 8 11 14 21

B B B B

Lenalidomide daily

*For a maximum of 8 cycles; for pts with PD Dex added (20mg day of and day following bortezomib): extension phase for pts in response

• 8 cohorts of 3–6 pts, with additional 10 pts enrolled at the MTD

Bortezomib, mg/m2

ResultsBaseline Characteristics (N = 12)

4 (33%)Prior bortezomib

83 IgG

Myeloma type, %

25Durie-Salmon stage III, %

17 IgA

9 (63%)Prior thalidomide

2 (17%)Prior lenalidomide

8 (66%)Prior SCT

4 (1-9)Median no. of prior therapies (range)

6 Relapsed and refractory, n

6 Relapsed, n

Disease status

42Male, %

59 (37–75)Median age, y (range)Characteristic

Response (n= 11*)

2

5–62

7–8

8–10

No. of Cycles

4

3

2

1

Cohort

CR: 1 of 3PR: 2 of 3

Bortezomib 1.3 mg/m2

+ lenalidomide 5 mg

PR: 1 of 3MR: 2 of 3

Bortezomib 1.0 mg/m2

+ lenalidomide 5 mg

PR: 1 of 2PD**: 1 of 2

Bortezomib 1.3 mg/m2

+ lenalidomide 10 mg

PR: 2 of 3PR: 1 of 3

Bortezomib 1.0 mg/m2

+ lenalidomide 10 mg

ResponseRegimen

*Evaluable **Dex added RR (CR + PR + MR) : 91%

Toxicity• No discontinuations

• No significant PNY, fatigue

• No DLT through first 3 cohorts

• One DLT in cohort 4– Grade 3 hyponatremia

• 4 additional pts will be enrolled in cohort 4– @ Bortezomib 1.3 mg/m2, lenalidomide 10 mg

• Dose reductions of bortezomib (1.3 to 1.0 mg/m2) (n=4), lenalidomide (10 to5 mg) (n=1) beyond cycle 2 (neutropenia, thrombocytopenia)

• MTD not yet reached

Based upon gene profiling:Bortezomib and Hsp90 inhibitor 17 AAG

Based upon cell signaling:Bortezomib and HDAC6 inhibitor tubacin

Based upon correlative science: Bortezomib and p38 MAPK inhibitor SCIO 469

Rationally Based Targets to Enhance Sensitivity orOvercome Resistance to Bortezomib

PROTEASOME

HSP

AGGRESOME

Micr

otub

ule

HSP

Proteasomaldegradation

BORTEZOMIB

Lysosomaldegradation

Proteasome Inhibition by Bortezomib

HSP

HSP

17AAG

BORTEZOMIB

Therapeutic Value of HSP inhibition FollowingBortezomib Treatment

10

20

30

40

50

Control

% C

ell d

eath

Bortezomib 17AAG Bortezomib

17AAG+

Dynein

AGGRESOME

Micr

otub

ule

Tubacin

Therapeutic value of Aggresome Inhibition by Tubacin

40

80

120

160

0 1.25 2.5 5 10 20

Tubacin (µM)P

rolif

erat

ion

(%

co

ntr

ol)

MM cell lines

Synergistic Anti-Proliferative Activity ofBortezomib and Tubacin

Tubacin

BORTEZOMIB0

20

40

60

80

100

0 5 10Tubacin (µM)

Pro

lifer

atio

n (

% c

on

tro

l)

10 nM

BORTEZOMIB

0 5100 5 100 5

PROTEASOMEAGGRESOME

Gene Microarray Predicts Clinical Response toProteasome Inhibitor

100

80

60

40

20

0-20

" 842 C/NE,pry no finishC2"

189 V/PD2

894 M/LOE-DM

708 D/D(4)115LOE

1155 D/n/a

333 Y/D(2)126

062 V/D2(187)E

1277 D/PD4?

309 Dh/D?LOE

826 V/D(2)102 no more avail.

1440 NW/D(2)152Exit-LOE

" 009 D/D(4)133,Dw/dex"

1254 NW/D(2)126

935 D/D(2)151exit

614 Y/B(6)62(nodex)

029 D-h/?SF?D(3);bcg-loeNE

058 V/D(4)191;LOE

1394 N/A(2)35

066 V/CR?F

581 N/C(2)80

" 699 V/A(4)10,dex-7,flagu"

1061 D/A(4)19

1235 NW/B(4)54

1151 D/B(4)61dex-5

423 Y/A(4)21PD-exit

139 V/n/a

181 V/A(2)28butdex-5…

814 V/A(4)27

498 C/n/a

613 Y/A(4)35; dex-5 why?

1049 D/A(4)34dex-4thenAE-exit

1053 D/A(4)1

1256 NW/n/a

"gb:M31159.1 /DEF=Human growth hormone-dependent insulin-l ike growth factor-binding protein mRNA, complete cds. /FEA=mRNA /GEN=IGFBP1 /DB_XREF=gi:183115 /UG=Hs.77326 insulin-l ike growth factor binding protein 3 /FL=gb:BC000013.1 gb:M31159.1"

"Consensus inc ludes gb:AB037738.1 /DEF=Homo sapiens mRNA for KIAA1317 prote in, par t ia l cds. /FEA=mRNA /GEN=KIAA1317 /PROD=KIAA1317 prote in /DB_XREF=gi :7243014 /UG=Hs.272254 KIAA1317 prote in"

"Consensus inc ludes gb :BE552347 /FEA=EST /DB_XREF=gi :9794039 /DB_XREF=est :hy06d10.x1 /CLONE=IMAGE:3196531 /UG=Hs.97319 ESTs, Weak ly s im i la r to DREAM pro te in H.sap iens"

"gb :NM_024688 .1 /DEF=Homo sap iens hypo the t i ca l p ro te in FLJ13031 (FLJ13031) , mRNA. /FEA=mRNA /GEN=FLJ13031 /PROD=hypo the t i ca l p ro te in FLJ13031 /DB_XREF=g i :13375961 /UG=Hs.97757 hypo the t i ca l p ro te in FLJ13031 /FL=gb :NM_024688 .1 "

C o n s e n s u s i n c l u d e s g b : B F 4 3 5 5 1 3 / F E A = E S T / D B _ X R E F = g i : 1 1 4 4 7 8 0 1 / D B _ X R E F = e s t : n a c 3 2 b 0 2 . x 1 / C L O N E = I M A G E : 3 3 9 4 8 7 5 / U G = H s . 2 2 7 8 0 6 r a s G T P a s e a c t i v a t i n g p r o t e i n - l i k e / F L = g b : A F 0 4 7 7 1 1 . 1 g b : N M _ 0 0 4 8 4 1 . 1

"gb :NM_023925 .1 /DEF=Homo sap iens hypo the t i ca l p ro te in FLJ22569 (FLJ22569) , mRNA. /FEA=mRNA /GEN=FLJ22569 /PROD=hypo the t i ca l p ro te in FLJ22569 /DB_XREF=g i :12965192 /UG=Hs.234355 hypo the t i ca l p ro te in FLJ22569 /FL=gb :NM_023925 .1 "

C o n s e n s u s i n c l u d e s g b : B F 5 1 4 5 0 9 / F E A = E S T / D B _ X R E F = g i : 1 1 5 9 9 6 8 8 / D B _ X R E F = e s t : U I - H - B W 1 - a n f - g - 0 3 - 0 - U I . s 1 / C L O N E = I M A G E : 3 0 8 2 1 8 0 / U G = H s . 2 6 2 5 7 1 E S T s

"gb:NM_000072.1 /DEF=Homo sapiens CD36 antigen (collagen type I receptor, thrombospondin receptor) (CD36), mRNA. /FEA=mRNA /GEN=CD36 /PROD=CD36 antigen (collagen type I receptor,thrombospondin receptor) /DB_XREF=gi:4557418 /UG=Hs.75613 CD36 antigen (co.

" g b : M 1 4 0 1 6 . 1 / D E F = H u m a n u r o p o r p h y r i n o g e n d e c a r b o x y l a s e m R N A , c o m p l e t e c d s . / F E A = m R N A / G E N = U R O D / D B _ X R E F = g i : 3 4 0 1 8 0 / U G = H s . 7 8 6 0 1 u r o p o r p h y r i n o g e n d e c a r b o x y l a s e / F L = g b : B C 0 0 1 7 7 8 . 1 g b : M 1 4 0 1 6 . 1 g b : A F 1 0 4 4 2 1 . 1 g b : A F 1 0 4 4 2 2 . 1 g b : A F 1 0 4 4 2 3 . 1 g b : A F 1 0 4 4 2 4 .

"gb:NM_002099.2 /DEF=Homo sapiens glycophorin A ( includes MN blood group) (GYPA), mRNA. /FEA=mRNA /GEN=GYPA /PROD=glycophorin A precursor /DB_XREF=gi:8051602 /UG=Hs.108694 glycophorin A ( includes MN blood group) /FL=gb:BC005319.1 gb:U00177.1 gb:L31.

"gb:NM_017488.1 /DEF=Homo sapiens adducin 2 (beta) (ADD2), transcript variant beta-4, mRNA. /FEA=mRNA /GEN=ADD2 /PROD=adducin 2, isoform e /DB_XREF=gi:9257189 /UG=Hs.247423 adducin 2 (beta) /FL=gb:NM_017488.1"

"gb:BC001207.1 /DEF=Homo sapiens, Similar to Dlxin-1, clone MGC:3210, mRNA, complete cds. /FEA=mRNA /PROD=Similar to Dlxin-1 /DB_XREF=gi:12654730 /UG=Hs.7457 MAGE1 protein /FL=gb:BC001207.1"

"Consensus inc ludes gb:X54741.1 /DEF=Human CYPXIB2 gene for a ldosterone synthase. /FEA=mRNA /GEN=human CYPXIB2 /PROD=aldosterone synthase (P-450aldo) /DB_XREF=gi :35199 /UG=Hs.184927 cytochrome P450, subfami ly XIB (stero id 11-beta-hydroxylase) , polypep.

"gb:NM_005461.1 /DEF=Homo sapiens Kreisler (mouse) maf-related leucine zipper homolog (KRML), mRNA. /FEA=mRNA /GEN=KRML /PROD=Kreisler (mouse) maf-related leucine zipperhomolog /DB_XREF=gi:4885446 /UG=Hs.169487 Kreisler (mouse) maf-related leucine zipper.

"gb:NM_000943.1 /DEF=Homo sapiens peptidylprolyl isomerase C (cyclophil in C) (PPIC), mRNA. /FEA=mRNA /GEN=PPIC /PROD=peptidylprolyl isomerase C (cyclophil in C) /DB_XREF=gi:4505990 /UG=Hs.110364 peptidylprolyl isomerase C (cyclophil in C) /FL=gb:BC002678.1 gb.

C o n s e n s u s i n c l u d e s g b : B E 9 6 2 7 4 9 / F E A = E S T / D B _ X R E F = g i : 1 1 7 6 5 9 6 8 / D B _ X R E F = e s t : 6 0 1 6 5 6 1 4 3 R 1 / C L O N E = I M A G E : 3 8 5 5 7 5 4 / U G = H s . 1 1 0 3 6 4 p e p t i d y l p r o l y l i s o m e r a s e C ( c y c l o p h i l i n C ) / F L = g b : B C 0 0 2 6 7 8 . 1 g b : N M _ 0 0 0 9 4 3 . 1

"gb :NM_014100.1 /DEF=Homo sap iens PRO1770 pro te in (PRO1770) , mRNA. /FEA=mRNA /GEN=PRO1770 /PROD=PRO1770 pro te in /DB_XREF=g i :7662612 /UG=Hs.196972 PRO1770 pro te in /FL=gb:AF118075.1 gb :NM_014100.1"

"gb:NM_000417.1 /DEF=Homo sapiens interleukin 2 receptor, alpha (IL2RA), mRNA. /FEA=mRNA /GEN=IL2RA /PROD=interleukin 2 receptor, alpha chain precursor /DB_XREF=gi:4557666 /UG=Hs.1724 interleukin 2 receptor, alpha /FL=gb:NM_000417.1"

C o n s e n s u s i n c l u d e s g b : B F 0 0 2 0 7 4 / F E A = E S T / D B _ X R E F = g i : 1 0 7 0 2 3 4 9 / D B _ X R E F = e s t : 7 g 9 8 f 0 7 . x 1 / C L O N E = I M A G E : 3 3 1 4 5 3 3 / U G = H s . 1 5 6 1 5 8 E S T s

C o n s e n s u s i n c l u d e s g b : A A 8 0 6 9 6 5 / F E A = E S T / D B _ X R E F = g i : 2 8 7 6 5 4 1 / D B _ X R E F = e s t : o c 3 4 c 0 6 . s 1 / C L O N E = I M A G E : 1 3 5 1 5 9 4 / U G = H s . 1 0 6 7 7 1 E S T s

"Consensus includes gb:AL050350 /DEF=Human DNA sequence from clone 261K5 on chromosome 6q21-22.1. Contains the 3 part of the gene for a novel organic cation transporter (BAC ORF RG331P03), the DDO gene for D-aspartate oxidase (EC 1.4.3.1), ESTs, STSs, GSSs and .

"Consensus i nc ludes gb :BF061074 /FEA=EST /DB_XREF=g i :10819984 /DB_XREF=es t :7 i80c08 .x1 /CLONE=IMAGE:3341006 /UG=Hs .131954 H2A h i s tone fam i l y , member D /FL=gb :NM_003510 .1 "

"gb:NM_023914.1 /DEF=Homo sapiens G protein-coupled receptor 86 (GPR86), mRNA. /FEA=mRNA /GEN=GPR86 /PROD=G protein-coupled receptor 86 /DB_XREF=gi:13194202 /UG=Hs.13040 G protein-coupled receptor 86 /FL=gb:AF295368.1 gb:NM_023914.1 gb:AF178982.1 .

"Consensus inc ludes gb :AK001225.1 /DEF=Homo sap iens cDNA FLJ10363 f i s , c lone NT2RM2001312. /FEA=mRNA /DB_XREF=g i :7022347 /UG=Hs.301157 Homo sap iens cDNA FLJ10363 f i s , c lone NT2RM2001312"

C o n s e n s u s i n c l u d e s g b : A I 6 8 4 4 3 9 / F E A = E S T / D B _ X R E F = g i : 4 8 9 5 7 3 3 / D B _ X R E F = e s t : w a 8 2 a 0 7 . x 1 / C L O N E = I M A G E : 2 3 0 2 6 4 4 / U G = H s . 3 3 1 0 9 9 E S T s

C o n s e n s u s i n c l u d e s g b : N 3 2 0 5 1 / F E A = E S T / D B _ X R E F = g i : 1 1 5 2 4 5 0 / D B _ X R E F = e s t : y w 9 6 h 0 2 . s 1 / C L O N E = I M A G E : 2 6 0 1 1 5 / U G = H s . 4 0 1 7 3 E S T s

"gb :NM_017535 .1 /DEF=Homo sap iens hypo the t i ca l p ro te in DKFZp566H0824 (DKFZp566H0824) , mRNA. /FEA=mRNA /GEN=DKFZp566H0824 /PROD=hypo the t i ca l p ro te in DKFZp566H0824 /DB_XREF=g i :8922158 /UG=Hs .279803 hypo the t i ca l p ro te in DKFZp566H0824 /FL=gb :N .

"gb:BC005305.1 /DEF=Homo sapiens, Similar to collagen, type IV, alpha 6, clone MGC:12376, mRNA, complete cds. /FEA=mRNA /PROD=Similar to collagen, type IV, alpha 6 /DB_XREF=gi:13529040 /UG=Hs.408 collagen, type IV, alpha 6 /FL=gb:BC005305.1"

"Consensus inc ludes gb :AC005578 /DEF=Homo sap iens ch romosome 19 , cosmid F20887 /FEA=CDS_1 /DB_XREF=g i :3510237 /UG=Hs.247732 Homo sap iens ch romosome 19 , cosmid F20887"

"gb:NM_003728.1 /DEF=Homo sapiens unc5 (C.e legans homolog) c (UNC5C), mRNA. /FEA=mRNA /GEN=UNC5C /PROD=unc5 (C.e legans homolog) c /DB_XREF=gi :4507836 /UG=Hs.44553 unc5 (C.e legans homolog) c /FL=gb:AF055634.1 gb:NM_003728.1"

"Consensus includes gb:U76376.1 /DEF=Homo sapiens activator of apoptosis Hrk (HRK) mRNA, complete cds. /FEA=mRNA /GEN=HRK /PROD=activator of apoptosis Hrk /DB_XREF=gi:1923234 /UG=Hs.87247 harakiri, BCL2-interacting protein (contains only BH3 domain) /FL=gb.

"Consensus inc ludes gb :AK001151.1 /DEF=Homo sap iens cDNA FLJ10289 f i s , c lone MAMMA1002319. /FEA=mRNA /DB_XREF=g i :7022224 /UG=Hs.296538 Homo sap iens cDNA FLJ10289 f i s , c lone MAMMA1002319"

C o n s e n s u s i n c l u d e s g b : B F 6 6 8 9 5 0 / F E A = E S T / D B _ X R E F = g i : 1 1 9 4 2 8 4 5 / D B _ X R E F = e s t : 6 0 2 1 2 3 0 6 9 F 1 / C L O N E = I M A G E : 4 2 8 0 1 5 3 / U G = H s . 1 0 3 5 1 K I A A 0 3 0 8 p r o t e i n

"gb:NM_004415.1 /DEF=Homo sapiens desmoplakin (DPI, DPII) (DSP), mRNA. /FEA=mRNA /GEN=DSP /PROD=desmoplakin (DPI, DPII) /DB_XREF=gi:4758199 /UG=Hs.74316 desmoplakin (DPI, DPII) /FL=gb:M77830.3 gb:NM_004415.1"

Consensus inc ludes gb :AF070565 .1 /DEF=Homo sap iens c lone 24425 mRNA sequence . /FEA=mRNA /DB_XREF=g i :3387933 /UG=Hs .13436 Homo sap iens c lone 24425 mRNA sequence

"gb:NM_005525.1 /DEF=Homo sap iens hydroxystero id (11-beta) dehydrogenase 1 (HSD11B1) , mRNA. /FEA=mRNA /GEN=HSD11B1 /PROD=hydroxystero id (11-beta) dehydrogenase 1 /DB_XREF=gi :5031764 /UG=Hs.275215 hydroxystero id (11-beta) dehydrogenase 1 /FL=gb.

C o n s e n s u s i n c l u d e s g b : B E 0 4 8 5 7 1 / F E A = E S T / D B _ X R E F = g i : 8 3 6 5 6 2 4 / D B _ X R E F = e s t : h r 5 0 g 0 3 . x 1 / C L O N E = I M A G E : 3 1 3 1 9 5 6 / U G = H s . 1 0 8 7 8 5 E S T s

"gb:NM_015148.1 /DEF=Homo sap iens KIAA0135 pro te in (KIAA0135) , mRNA. /FEA=mRNA /GEN=KIAA0135 /PROD=KIAA0135 pro te in /DB_XREF=gi :8923825 /UG=Hs.79337 KIAA0135 pro te in /FL=gb:NM_015148.1"

"gb :NM_025047 .1 /DEF=Homo sap iens hypo the t i ca l p ro te in FLJ22595 (FLJ22595) , mRNA. /FEA=mRNA /GEN=FLJ22595 /PROD=hypo the t i ca l p ro te in FLJ22595 /DB_XREF=g i :13376573 /UG=Hs.287702 hypo the t i ca l p ro te in FLJ22595 /FL=gb :NM_025047 .1 "

"gb:NM_000148.1 /DEF=Homo sapiens fucosyl t ransferase 1 (galactoside 2-a lpha-L- fucosyl t ransferase, Bombay phenotype inc luded) (FUT1), mRNA. /FEA=mRNA /GEN=FUT1 /PROD=fucosyl t ransferase 1 (galactoside2-alpha-L- fucosyl t ransferase, Bombay phenotype inc luded) .

"gb:NM_018833.1 /DEF=Homo sapiens ATP-binding cassette, sub-family B (MDRTAP), member 3 (ABCB3), transcript variant 2, mRNA. /FEA=mRNA /GEN=ABCB3 /PROD=ATP-binding cassette, sub-family B, member 3,isoform 2 /DB_XREF=gi:9961247 /UG=Hs.502 ATP-binding casset.

"gb:NM_003219.1 /DEF=Homo sapiens te lomerase reverse t ranscr ip tase (TERT), mRNA. /FEA=mRNA /GEN=TERT /PROD=te lomerase reverse t ranscr ip tase /DB_XREF=gi :4507438 /UG=Hs.115256 te lomerase reverse t ranscr ip tase /FL=gb:AF015950.1 gb:AF018167.1 gb:NM_00.

"gb:NM_006329.1 /DEF=Homo sapiens f ibul in 5 (FBLN5), mRNA. /FEA=mRNA /GEN=FBLN5 /PROD=f ibul in 5 /DB_XREF=gi :5453649 /UG=Hs.11494 f ibul in 5 /FL=gb:AF093118.1 gb:AF112152.1 gb:NM_006329.1"

"gb :NM_018279.1 /DEF=Homo sap iens hypo the t i ca l p ro te in FLJ10936 (FLJ10936) , mRNA. /FEA=mRNA /GEN=FLJ10936 /PROD=hypo the t i ca l p ro te in FLJ10936 /DB_XREF=g i :8922782 /UG=Hs.7337 hypo the t i ca l p ro te in FLJ10936 /FL=gb :NM_018279.1"

Consensus i nc l udes gb :AL563297 /FEA=EST /DB_XREF=g i : 12912551 /DB_XREF=es t :AL563297 /CLONE=CS0DD004YH24 (3 p r ime ) /UG=Hs .183874 cu l l i n 4A

Consensus includes gb:X92110.1 /DEF=H.sapiens mRNA for hcgVII I protein. /FEA=mRNA /DB_XREF=gi:1216163 /UG=Hs.153618 HCGVII I -1 protein

"Consensus inc ludes gb :AK022897 .1 /DEF=Homo sap iens cDNA FLJ12835 f i s , c lone NT2RP2003165 . /FEA=mRNA /DB_XREF=g i :10434555 /UG=Hs.306641 Homo sap iens cDNA FLJ12835 f i s , c lone NT2RP2003165"

"Consensus i nc ludes gb :AA788711 /FEA=EST /DB_XREF=g i : 2848831 /DB_XREF=es t :ag40g07 .s1 /CLONE=IMAGE:1119324 /UG=Hs .179573 co l l agen , t ype I , a l pha 2 /FL=gb :J03464 .1 gb :NM_000089 .1 "

Consensus i nc ludes gb :AW512196 /FEA=EST /DB_XREF=g i :7150274 /DB_XREF=es t : xx71e04 .x1 /CLONE=IMAGE:2849118 /UG=Hs .234392 p la te le t -ac t i va t i ng f ac to r ace ty lhyd ro lase 2 (40kD)

"gb:BC004492.1 /DEF=Homo sapiens, c lone MGC:11081, mRNA, complete cds. /FEA=mRNA /PROD=Unknown (prote in for MGC:11081) /DB_XREF=gi :13325369 /UG=Hs.288771 DKFZP586A0522 prote in /FL=gb:BC004492.1"

C o n s e n s u s i n c l u d e s g b : A W 1 9 4 5 4 3 / F E A = E S T / D B _ X R E F = g i : 6 4 7 3 3 8 1 / D B _ X R E F = e s t : x b 2 7 c 0 2 . x 1 / C L O N E = I M A G E : 2 5 7 7 5 0 6 / U G = H s . 2 3 4 5 7 3 H o m o s a p i e n s m R N A f o r T L 1 3 2

C o n s e n s u s i n c l u d e s g b : W 5 2 0 1 0 / F E A = E S T / D B _ X R E F = g i : 1 3 4 9 7 3 4 / D B _ X R E F = e s t : z c 9 2 g 1 2 . r 1 / C L O N E = I M A G E : 3 3 8 6 6 2 / U G = H s . 1 9 1 3 7 9 E S T s

"gb:D38145.1 /DEF=Human mRNA for prostacyc l in synthase, complete cds. /FEA=mRNA /GEN=PTGIS /PROD=prostacyc l in synthase /DB_XREF=gi :537948 /UG=Hs.302085 prostaglandin I2 (prostacyc l in) synthase /FL=gb:D38145.1"

C o n s e n s u s i n c l u d e s g b : A W 0 0 2 3 9 0 / F E A = E S T / D B _ X R E F = g i : 5 8 4 9 3 0 6 / D B _ X R E F = e s t : w u 6 1 d 0 2 . x 1 / C L O N E = I M A G E : 2 5 2 4 5 1 5 / U G = H s . 1 9 7 7 2 3 E S T s

C o n s e n s u s i n c l u d e s g b : A A 9 7 2 7 1 1 / F E A = E S T / D B _ X R E F = g i : 3 1 4 7 8 9 1 / D B _ X R E F = e s t : o p 9 0 e 0 7 . s 1 / C L O N E = I M A G E : 1 5 8 4 1 3 2 / U G = H s . 1 7 3 0 8 1 K I A A 0 5 3 0 p r o t e i n

"gb :NM_014723 .1 /DEF=Homo sap iens syn taph i l i n (K IAA0374) , mRNA. /FEA=mRNA /GEN=KIAA0374 /PROD=syn taph i l i n /DB_XREF=g i :7662081 /UG=Hs .323833 syn taph i l i n /FL=gb :AB002372 .1 gb :AF187733 .1 gb :NM_014723 .1 "

" C o n s e n s u s i n c l u d e s g b : A U 1 4 7 5 0 6 / F E A = E S T / D B _ X R E F = g i : 1 1 0 0 9 0 2 7 / D B _ X R E F = e s t : A U 1 4 7 5 0 6 / C L O N E = M A M M A 1 0 0 0 8 8 0 / U G = H s . 2 8 8 5 3 7 H o m o s a p i e n s c D N A F L J 1 2 1 9 9 f i s , c l o n e M A M M A 1 0 0 0 8 8 0 "

"Consensus inc ludes gb:W80619 /FEA=EST /DB_XREF=gi :1391636 /DB_XREF=est :zh50b12.s1 /CLONE=IMAGE:415487 /UG=Hs.269636 ESTs, Weakly s imi lar to ALU1_HUMAN ALU SUBFAMILY J SEQUENCE CONTAMINATION WARNING ENTRY H.sapiens"

Consensus inc ludes gb :AF070575 .1 /DEF=Homo sap iens c lone 24407 mRNA sequence . /FEA=mRNA /DB_XREF=g i :3387946 /UG=Hs .12432 Homo sap iens c lone 24407 mRNA sequence

"gb:NM_006720.1 /DEF=Homo sapiens actin binding LIM protein 1 (ABLIM), transcript variant ABLIM-s, mRNA. /FEA=mRNA /GEN=ABLIM /PROD=actin-binding LIM protein 1, isoform s /DB_XREF=gi:5921987 /UG=Hs.158203 actin binding LIM protein 1 /FL=gb:D31883.1 gb:NM_006720.

"Consensus includes gb:AB014511.1 /DEF=Homo sapiens mRNA for KIAA0611 protein, part ial cds. /FEA=mRNA /GEN=KIAA0611 /PROD=KIAA0611 protein /DB_XREF=gi:3327035 /UG=Hs.70604 ATPase, Class I I , type 9A"

"gb :AF119863.1 /DEF=Homo sap iens PRO2160 mRNA, comple te cds . /FEA=mRNA /PROD=PRO2160 /DB_XREF=g i :7770162 /UG=Hs.112844 materna l l y expressed 3 /FL=gb:AF119863.1"

C o n s e n s u s i n c l u d e s g b : A I 6 3 3 7 7 4 / F E A = E S T / D B _ X R E F = g i : 4 6 8 5 1 0 4 / D B _ X R E F = e s t : t t 2 8 d 0 6 . x 1 / C L O N E = I M A G E : 2 2 4 2 0 9 1 / U G = H s . 6 7 0 5 K I A A 1 0 4 2 p r o t e i n / F L = g b : A B 0 2 8 9 6 5 . 1 g b : N M _ 0 1 4 9 6 5 . 1

"gb:AF313468.1 /DEF=Homo sapiens dendri t ic cel l -associated C-type lect in-1 mRNA, complete cds. /FEA=mRNA /PROD=dendri t ic cel l -associated C-type lect in-1 /DB_XREF=gi:13649707 /FL=gb:AF313468.1"

"Consensus inc ludes gb:AK025363.1 /DEF=Homo sap iens cDNA: FLJ21710 f is , c lone COL10087. /FEA=mRNA /DB_XREF=gi :10437865 /UG=Hs.306807 Homo sap iens cDNA: FLJ21710 f is , c lone COL10087"

"Consensus i nc l udes gb :AU134977 /FEA=EST /DB_XREF=g i : 10995516 /DB_XREF=es t :AU134977 /CLONE=PLACE1000926 /UG=Hs .322149 Human c l one 137308 mRNA, pa r t i a l cds "

"gb:NM_005295.1 /DEF=Homo sapiens G protein-coupled receptor 22 (GPR22), mRNA. /FEA=CDS /GEN=GPR22 /PROD=G protein-coupled receptor 22 /DB_XREF=gi:4885308 /UG=Hs.248121 G protein-coupled receptor 22 /FL=gb:NM_005295.1"

"gb:NM_024547.1 /DEF=Homo sap iens KIAA0467 pro te in (K IAA0467) , mRNA. /FEA=mRNA /GEN=KIAA0467 /PROD=hypothet ica l p ro te in FLJ23425 /DB_XREF=gi :13386459 /UG=Hs.301943 KIAA0467 pro te in /FL=gb:NM_024547.1"

Consensus inc ludes gb:AJ276803.1 /DEF=Homo sap iens mRNA for pro tocadher in (PCDHY gene) . /FEA=mRNA /GEN=PCDHY /PROD=protocadher in /DB_XREF=gi :10803410 /UG=Hs.159156 pro tocadher in 11

"gb:AB037925.1 /DEF=Homo sapiens MAIL mRNA, complete cds. /FEA=mRNA /GEN=MAIL /DB_XREF=gi :13516830 /UG=Hs.301183 Homo sapiens MAIL mRNA, complete cds /FL=gb:AB037925.1"

C o n s e n s u s i n c l u d e s g b : A W 1 7 3 1 6 6 / F E A = E S T / D B _ X R E F = g i : 6 4 3 9 1 1 4 / D B _ X R E F = e s t : x j 8 4 b 1 1 . x 1 / C L O N E = I M A G E : 2 6 6 3 9 0 1 / U G = H s . 2 4 3 4 6 8 E S T s

"Clus te r Inc l . AL041852:DKFZp434D0918_r1 Homo sap iens cDNA, 5 end /c lone=DKFZp434D0918 /c lone_end=5 /gb=AL041852 /g i=5421198 /ug=Hs.6343 / len=661"

"Consensus includes gb:AK000270.1 /DEF=Homo sapiens cDNA FLJ20263 f is, c lone COLF7804, highly simi lar to AJ131693 Homo sapiens mRNA for AKAP450 protein. /FEA=mRNA /DB_XREF=gi:7020239 /UG=Hs.164036 Homo sapiens AKAP350C mRNA sequence, al ternat ively .

C o n s e n s u s i n c l u d e s g b : A I 8 2 1 4 7 7 / F E A = E S T / D B _ X R E F = g i : 5 4 4 0 5 5 6 / D B _ X R E F = e s t : n j 4 5 a 0 6 . x 5 / C L O N E = I M A G E : 9 9 5 4 1 0 / U G = H s . 1 3 6 5 4 4 E S T s

"gb :NM_025092 .1 /DEF=Homo sap iens hypo the t i ca l p ro te in FLJ22635 (FLJ22635) , mRNA. /FEA=mRNA /GEN=FLJ22635 /PROD=hypo the t i ca l p ro te in FLJ22635 /DB_XREF=g i :13376651 /UG=Hs.288529 hypo the t i ca l p ro te in FLJ22635 /FL=gb :NM_025092 .1 "

"Consensus inc ludes gb :AK022442.1 /DEF=Homo sap iens cDNA FLJ12380 f i s , c lone MAMMA1002556. /FEA=mRNA /DB_XREF=g i :10433838 /UG=Hs.300934 Homo sap iens cDNA FLJ12380 f i s , c lone MAMMA1002556"

C o n s e n s u s i n c l u d e s g b : W 8 6 6 5 9 / F E A = E S T / D B _ X R E F = g i : 1 4 0 0 5 3 5 / D B _ X R E F = e s t : z h 6 4 d 0 8 . s 1 / C L O N E = I M A G E : 4 1 6 8 4 7 / U G = H s . 1 1 8 3 4 8 E S T s

"Consensus includes gb:AB023203.1 /DEF=Homo sapiens mRNA for KIAA0986 protein, part ia l cds. /FEA=mRNA /GEN=KIAA0986 /PROD=KIAA0986 protein /DB_XREF=gi :4589615 /UG=Hs.53542 KIAA0986 protein"

"gb:NM_007116.1 /DEF=Homo sapiens tenasc in XA (TNXA), mRNA. /FEA=mRNA /GEN=TNXA /PROD=tenasc in XA /DB_XREF=gi :6005907 /UG=Hs.283750 tenasc in XA /FL=gb:U24488.1 gb:NM_007116.1"

"gb:U50157.1 /DEF=Human cAMP-spec i f ic phosphodiesterase HPDE4D1 var iant (PDE4D) mRNA, complete cds. /FEA=CDS /GEN=PDE4D /PROD=cAMP-spec i f ic phosphodiesterase HPDE4D1 var iant /DB_XREF=gi :1236954 /UG=Hs.172081 phosphodiesterase 4D, cAMP-spec i f ic .

Consensus inc ludes gb:AL049278.1 /DEF=Homo sap iens mRNA; cDNA DKFZp564I153 ( f rom c lone DKFZp564I153) . /FEA=mRNA /DB_XREF=gi :4500033 /UG=Hs.16074 Homo sap iens mRNA; cDNA DKFZp564I153 ( f rom c lone DKFZp564I153)

"Consensus includes gb:AL139327 /DEF=Human DNA sequence from clone RP11-408E5 on chromosome 13q11-12.2 Contains an FSH primary respone homolog 1 (FSHPRH1) pseudogene, two genes for novel proteins, a gene for an orthologue of mouse tubulin alpha 3 (TUBA3).

C o n s e n s u s i n c l u d e s g b : A I 6 5 6 7 4 5 / F E A = E S T / D B _ X R E F = g i : 4 7 4 0 7 2 4 / D B _ X R E F = e s t : t t 5 3 h 0 6 . x 1 / C L O N E = I M A G E : 2 2 4 4 5 3 9 / U G = H s . 1 9 7 4 2 3 E S T s

"gb:AF332234.1 /DEF=Homo sapiens testis transcript Y 8 (TTY8) mRNA, complete cds, alternatively spliced. /FEA=mRNA /GEN=TTY8 /PROD=transcript Y 8 /DB_XREF=gi:13161107 /UG=Hs.326784 Homo sapiens testis transcript Y 6 (TTY6) mRNA, complete cds, alternatively spliced .

C o n s e n s u s i n c l u d e s g b : A I 6 5 5 9 5 0 / F E A = E S T / D B _ X R E F = g i : 4 7 3 9 9 2 9 / D B _ X R E F = e s t : t t 4 1 g 0 9 . x 1 / C L O N E = I M A G E : 2 2 4 3 3 9 2 / U G = H s . 1 9 7 7 0 5 E S T s

"gb:NM_003240.1 /DEF=Homo sapiens endometrial bleeding associated factor (left-right determination, factor A; transforming growth factor beta superfamily) (EBAF), mRNA. /FEA=mRNA /GEN=EBAF /PROD=transforming growth factor, beta 4 /DB_XREF=gi:4503440 /UG=Hs.25195 en.

C o n s e n s u s i n c l u d e s g b : A W 0 1 4 3 7 4 / F E A = E S T / D B _ X R E F = g i : 5 8 6 3 1 3 1 / D B _ X R E F = e s t : U I - H - B I 0 - a a c - a - 0 4 - 0 - U I . s 1 / C L O N E = I M A G E : 2 7 0 8 6 4 6 / U G = H s . 1 4 4 8 4 9 E S T s

"Consensus inc ludes gb:AI476456 /FEA=EST /DB_XREF=gi :4329501 /DB_XREF=est : tm16f11.x1 /CLONE=IMAGE:2156781 /UG=Hs.136581 ESTs, Weakly s imi lar to ARNO_HUMAN ARF NUCLEOTIDE-BINDING SITE OPENER H.sapiens"

C o n s e n s u s i n c l u d e s g b : A I 2 0 0 8 0 4 / F E A = E S T / D B _ X R E F = g i : 3 7 5 3 4 1 0 / D B _ X R E F = e s t : q f 6 2 b 1 1 . x 1 / C L O N E = I M A G E : 1 7 5 4 5 8 9 / U G = H s . 9 8 6 1 2 E S T s

" C o n s e n s u s i n c l u d e s g b : B G 1 0 6 9 1 9 / F E A = E S T / D B _ X R E F = g i : 1 2 6 0 0 7 6 5 / D B _ X R E F = e s t : 6 0 2 2 9 1 3 2 6 F 1 / C L O N E = I M A G E : 4 3 8 6 0 0 7 / U G = H s . 1 3 1 8 8 6 H o m o s a p i e n s c D N A : F L J 2 2 1 1 3 f i s , c l o n e H E P 1 8 4 1 8 "

"gb:NM_016332.1 /DEF=Homo sapiens se lenoprote in X, 1 (SEPX1), mRNA. /FEA=mRNA /GEN=SEPX1 /PROD=selenoprote in X, 1 /DB_XREF=gi :7706510 /UG=Hs.279623 se lenoprote in X, 1 /FL=gb:AF187272.1 gb:BC003127.1 gb:AF166124.1 gb:NM_016332.1"

C o n s e n s u s i n c l u d e s g b : A W 2 6 9 8 3 4 / F E A = E S T / D B _ X R E F = g i : 6 6 5 6 8 6 4 / D B _ X R E F = e s t : x v 4 5 g 1 2 . x 1 / C L O N E = I M A G E : 2 8 1 6 1 3 4 / U G = H s . 1 5 0 3 9 5 p h o s p h o d i e s t e r a s e 7 A / F L = g b : L 1 2 0 5 2 . 1

C o n s e n s u s i n c l u d e s g b : B F 3 1 5 0 9 3 / F E A = E S T / D B _ X R E F = g i : 1 1 2 6 3 2 8 8 / D B _ X R E F = e s t : 6 0 1 9 0 2 5 3 2 F 1 / C L O N E = I M A G E : 4 1 3 5 1 5 8 / U G = H s . 2 2 2 9 3 E S T s

"Consensus includes gb:NM_020300.1 /DEF=Homo sapiens microsomal glutathione S-transferase 1 (MGST1), mRNA. /FEA=CDS /GEN=MGST1 /PROD=microsomal glutathione S-transferase 1 /DB_XREF=gi:9945305 /UG=Hs.790 microsomal glutathione S-transferase 1 /FL=gb:NM.

Consensus i nc ludes gb :A I220117 /FEA=EST /DB_XREF=g i :3802320 /DB_XREF=es t :qg89h11 .x1 /CLONE=IMAGE:1842405 /UG=Hs .790 m ic rosoma l g l u ta th ione S - t rans fe rase 1

"Consensus inc ludes gb :T15991 /FEA=EST /DB_XREF=g i :518153 /DB_XREF=es t : IB2413 /UG=Hs.7138 cho l ine rg ic recep to r , muscar in i c 3 /FL=gb :NM_000740 .1 "

"gb:AF055084.1 /DEF=Homo sapiens very large G-protein coupled receptor-1 (VLGR1) mRNA, complete cds. /FEA=mRNA /GEN=VLGR1 /PROD=very large G-protein coupled receptor-1 /DB_XREF=gi:5902965 /UG=Hs.153692 Homo sapiens cDNA FLJ14354 f is, clone Y79AA100.

Consensus includes gb:AJ275978.1 /DEF=Homo sapiens part ia l mRNA LAGE-2b for hypothet ical protein (LAGE-2 gene). /FEA=mRNA /GEN=LAGE-2 /PROD=hypothet ical protein /DB_XREF=gi:7208842 /UG=Hs.167379 cancertest is ant igen

Consensus inc ludes gb:AJ012833.1 /DEF=Homo sapiens mRNA for CTL-recognized ant igen on melanoma (CAMEL). /FEA=mRNA /GEN=CAMEL /PROD=CTL-recognized ant igen on melanoma (CAMEL) /DB_XREF=gi :3893216 /UG=Hs.87225 cancer test is ant igen 2

"gb:U87459.1 /DEF=Human auto immunogenic cancer test is ant igen NY-ESO-1 mRNA, complete cds. /FEA=mRNA /PROD=auto immunogenic cancer test is ant igen NY-ESO-1 /DB_XREF=gi :1890098 /UG=Hs.167379 cancer test is ant igen /FL=gb:U87459.1 gb:NM_001327.1"

"gb:AF038567.1 /DEF=Homo sapiens cancer ant igen-3 and cancer ant igen-3-ORF2 mRNA, complete cds. /FEA=mRNA /PROD=cancer ant igen-3-ORF2; cancer ant igen-3 /DB_XREF=gi :4104676 /FL=gb:AF038567.1"

"gb:NM_002363.1 /DEF=Homo sapiens melanoma antigen, family B, 1 (MAGEB1), mRNA. /FEA=mRNA /GEN=MAGEB1 /PROD=melanoma antigen, family B, 1 /DB_XREF=gi:4505078 /UG=Hs.73021 melanoma antigen, family B, 1 /FL=gb:NM_002363.1"

"gb:NM_005635.1 /DEF=Homo sapiens synovial sarcoma, X breakpoint 1 (SSX1), mRNA. /FEA=mRNA /GEN=SSX1 /PROD=synovial sarcoma, X breakpoint 1 /DB_XREF=gi:5032120 /UG=Hs.194759 synovial sarcoma, X breakpoint 1 /FL=gb:BC001003.2 gb:NM_005635.1"

"Consensus includes gb:X79200.1 /DEF=Homo spaiens mRNA for SYT-SSX protein. /FEA=mRNA /PROD=SYT-SSX protein /DB_XREF=gi:531107 /UG=Hs.289105 synovial sarcoma, X breakpoint 2"

"gb:BC002818.1 /DEF=Homo sapiens, Similar to synovial sarcoma, X breakpoint 2, clone MGC:3884, mRNA, complete cds. /FEA=mRNA /PROD=Similar to synovial sarcoma, X breakpoint 2 /DB_XREF=gi:12803942 /UG=Hs.289105 synovial sarcoma, X breakpoint 2 /FL=gb:BC002818.

"gb:BC001003.2 /DEF=Homo sapiens, synovial sarcoma, X breakpoint 1, c lone MGC:5162, mRNA, complete cds. /FEA=mRNA /PROD=synovial sarcoma, X breakpoint 1 /DB_XREF=gi:12803043 /UG=Hs.194759 synovial sarcoma, X breakpoint 1 /FL=gb:BC001003.2 gb:NM_005635.

"gb:BC005325.1 /DEF=Homo sapiens, synovial sarcoma, X breakpoint 4, c lone MGC:12411, mRNA, complete cds. /FEA=mRNA /PROD=synovial sarcoma, X breakpoint 4 /DB_XREF=gi:13529094 /UG=Hs.289105 synovial sarcoma, X breakpoint 2 /FL=gb:BC005325.1"

"gb:AF257500.1 /DEF=Homo sapiens SYTSSX4 fusion prote in (SSXTSSX4 fusion) mRNA, complete cds. /FEA=mRNA /GEN=SSXTSSX4 fusion /PROD=SYTSSX4 fusion prote in /DB_XREF=gi :11127694 /UG=Hs.289105 synovia l sarcoma, X breakpoint 2 /FL=gb:AF257500.1 gb:AF230662.

"Consensus inc ludes gb:BE966038 /FEA=EST /DB_XREF=gi :11771031 /DB_XREF=est :601659941R1 /CLONE=IMAGE:3905555 /UG=Hs.250863 ESTs, Weak ly s imi la r to ALU1_HUMAN ALU SUBFAMILY J SEQUENCE CONTAMINATION WARNING ENTRY H.sap iens"

C o n s e n s u s i n c l u d e s g b : A A 7 7 0 0 1 4 / F E A = E S T / D B _ X R E F = g i : 2 8 2 1 2 5 2 / D B _ X R E F = e s t : a h 8 1 h 0 2 . s 1 / C L O N E = 1 3 2 2 0 6 7 / U G = H s . 1 9 2 3 7 1 E S T s

"gb:AF167079.1 /DEF=Homo sapiens var iably charged X-B (VCXB) mRNA, complete cds. /FEA=mRNA /GEN=VCXB /PROD=var iably charged X-B /DB_XREF=gi :11934657 /UG=Hs.278906 var iable charge, X chromosome /FL=gb:AF167079.1"

"gb:NM_002364.1 /DEF=Homo sapiens melanoma antigen, family B, 2 (MAGEB2), mRNA. /FEA=mRNA /GEN=MAGEB2 /PROD=melanoma antigen, family B, 2 /DB_XREF=gi:4505080 /UG=Hs.113824 melanoma antigen, family B, 2 /FL=gb:AF015766.1 gb:NM_002364.1"

"gb:NM_016602.1 /DEF=Homo sapiens G protein-coupled receptor 2 (GPR2), mRNA. /FEA=mRNA /GEN=GPR2 /PROD=CC chemokine receptor 10 /DB_XREF=gi :7705315 /UG=Hs.278446 G protein-coupled receptor 2 /FL=gb:AF215981.1 gb:NM_016602.1 gb:AF208237.1"

C o n s e n s u s i n c l u d e s g b : A A 9 2 7 5 3 3 / F E A = E S T / D B _ X R E F = g i : 3 0 7 6 4 3 0 / D B _ X R E F = e s t : o m 7 1 b 0 5 . s 1 / C L O N E = I M A G E : 1 5 5 2 5 9 3 / U G = H s . 3 1 3 3 2 4 E S T s

"Consensus inc ludes gb:AW135330 /FEA=EST /DB_XREF=gi :6139463 /DB_XREF=est :UI -H-BI1-acb-h-10-0-UI .s1 /CLONE=IMAGE:2713963 /UG=Hs.245431 ESTs, Weakly s imi lar to PAG1_HUMAN PROSTATE-ASSOCIATED GENE PROTEIN 1 H.sap iens"

"gb:NM_004081.2 /DEF=Homo sapiens deleted in azoospermia (DAZ), mRNA. /FEA=mRNA /GEN=DAZ /PROD=deleted in azoospermia /DB_XREF=gi :6552325 /UG=Hs.70936 deleted in azoospermia /FL=gb:U21663.1 gb:NM_004081.2"

"gb:NM_020411.1 /DEF=Homo sapiens XAGE-1 prote in (XAGE-1), mRNA. /FEA=mRNA /GEN=XAGE-1 /PROD=XAGE-1 prote in /DB_XREF=gi :9966898 /UG=Hs.112208 XAGE-1 prote in /FL=gb:AF251237.1 gb:NM_020411.1"

C o n s e n s u s i n c l u d e s g b : Z 9 8 4 4 3 / F E A = E S T / D B _ X R E F = g i : 2 3 2 6 5 9 1 / D B _ X R E F = e s t : H S Z 9 8 4 4 3 / C L O N E = D K F Z p h t h m 1 _ 1 e 1 0 / U G = H s . 8 6 3 6 6 E S T s

C o n s e n s u s i n c l u d e s g b : A W 2 9 9 4 6 3 / F E A = E S T / D B _ X R E F = g i : 6 7 0 9 1 4 0 / D B _ X R E F = e s t : x s 5 0 e 0 3 . x 1 / C L O N E = I M A G E : 2 7 7 3 0 8 4 / U G = H s . 2 0 8 0 6 7 E S T s

"gb:BC006121.1 /DEF=Homo sapiens, c lone MGC:13000, mRNA, complete cds. /FEA=mRNA /PROD=Unknown (prote in for MGC:13000) /DB_XREF=gi :13543963 /FL=gb:BC006121.1"

C o n s e n s u s i n c l u d e s g b : A A 9 0 9 3 3 0 / F E A = E S T / D B _ X R E F = g i : 3 0 4 8 7 3 5 / D B _ X R E F = e s t : o m 0 9 g 0 5 . s 1 / C L O N E = I M A G E : 1 5 4 0 5 6 8 / U G = H s . 1 1 2 7 6 5 E S T s

C o n s e n s u s i n c l u d e s g b : A I 9 2 7 9 1 9 / F E A = E S T / D B _ X R E F = g i : 5 6 6 3 8 8 3 / D B _ X R E F = e s t : w p 0 3 d 1 1 . x 1 / C L O N E = I M A G E : 2 4 6 3 7 6 5 / U G = H s . 1 8 7 6 2 5 E S T s

" C o n s e n s u s i n c l u d e s g b : B E 6 7 3 4 4 5 / F E A = E S T / D B _ X R E F = g i : 1 0 0 3 3 9 8 6 / D B _ X R E F = e s t : 7 d 3 5 d 1 0 . x 1 / C L O N E = I M A G E : 3 2 4 9 2 3 5 / U G = H s . 2 2 0 4 9 H o m o s a p i e n s c h r o m o s o m e 1 9 , c o s m i d R 2 8 3 7 9 "

C o n s e n s u s i n c l u d e s g b : A I 8 2 7 9 0 6 / F E A = E S T / D B _ X R E F = g i : 5 4 4 8 6 6 4 / D B _ X R E F = e s t : w f 3 4 d 1 2 . x 1 / C L O N E = I M A G E : 2 3 5 7 4 9 5 / U G = H s . 2 8 5 4 9 1 E S T s

"Consensus inc ludes gb :AW664802 /FEA=EST /DB_XREF=g i :7457346 /DB_XREF=es t :h j09a06.x1 /CLONE=IMAGE:2981266 /UG=Hs.128494 ESTs, Weak ly s im i la r to EG:95B7.2 D.me lanogas te r "

C o n s e n s u s i n c l u d e s g b : A W 6 6 5 5 3 8 / F E A = E S T / D B _ X R E F = g i : 7 4 5 8 1 7 7 / D B _ X R E F = e s t : h i 9 2 c 1 0 . x 1 / C L O N E = I M A G E : 2 9 7 9 7 6 2 / U G = H s . 1 1 7 6 8 9 E S T s

C o n s e n s u s i n c l u d e s g b : H 2 8 9 1 5 / F E A = E S T / D B _ X R E F = g i : 8 9 9 8 2 5 / D B _ X R E F = e s t : y m 3 3 b 0 9 . s 1 / C L O N E = I M A G E : 4 9 7 6 6 / U G = H s . 1 1 7 6 8 9 E S T s

"gb:NM_002524.2 /DEF=Homo sapiens neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), mRNA. /FEA=mRNA /GEN=NRAS /PROD=neuroblastoma RAS viral (v-ras) oncogenehomolog /DB_XREF=gi:6006027 /UG=Hs.260523 neuroblastoma RAS viral (v-ras) oncogene.

"gb:BC001208.1 /DEF=Homo sapiens, Similar to hypothet ical protein LOC63929, clone MGC:3211, mRNA, complete cds. /FEA=mRNA /PROD=Similar to hypothet ical protein LOC63929 /DB_XREF=gi:12654732 /UG=Hs.182061 hypothet ical protein LOC63929 /FL=gb:BC001208.1"

Consensus i nc ludes gb :A I861913 /FEA=EST /DB_XREF=g i : 5526020 /DB_XREF=es t : t d17g05 .x1 /CLONE=IMAGE:2075960 /UG=Hs .143638 WD repea t doma in 4

Consensus inc ludes gb :AL353944.1 /DEF=Homo sap iens mRNA; cDNA DKFZp761J1112 ( f rom c lone DKFZp761J1112) . /FEA=mRNA /DB_XREF=g i :7669984 /UG=Hs.50115 Homo sap iens mRNA; cDNA DKFZp761J1112 ( f rom c lone DKFZp761J1112)

C o n s e n s u s i n c l u d e s g b : A W 9 8 3 6 9 1 / F E A = E S T / D B _ X R E F = g i : 8 1 7 5 2 8 3 / D B _ X R E F = e s t : R C 3 - H N 0 0 0 2 - 2 3 0 3 0 0 - 0 1 1 - a 1 1 / U G = H s . 1 4 5 8 0 9 E S T s

"gb:NM_014501.1 /DEF=Homo sapiens ubiquit in carrier protein (E2-EPF), mRNA. /FEA=mRNA /GEN=E2-EPF /PROD=ubiquit in carrier protein /DB_XREF=gi:7657045 /UG=Hs.174070 ubiquit in carrier protein /FL=gb:M91670.1 gb:NM_014501.1"

"Consensus inc ludes gb:H29876 /FEA=EST /DB_XREF=gi :900786 /DB_XREF=est :yp44d05.s1 /CLONE=IMAGE:190281 /UG=Hs.290874 ESTs, Weakly s imi lar to ALU8_HUMAN ALU SUBFAMILY SX SEQUENCE CONTAMINATION WARNING ENTRY H.sapiens"

"gb:NM_016049.1 /DEF=Homo sap iens CGI-112 pro te in (LOC51016) , mRNA. /FEA=mRNA /GEN=LOC51016 /PROD=CGI-112 pro te in /DB_XREF=gi :7705615 /UG=Hs.271614 CGI-112 pro te in /FL=gb:BC002491.1 gb:AF151870.1 gb:NM_016049.1"

Consensus inc ludes gb :AL359571.1 /DEF=Homo sap iens mRNA; cDNA DKFZp547G043 ( f rom c lone DKFZp547G043) . /FEA=mRNA /DB_XREF=g i :8655630 /UG=Hs.12772 K IAA1565 p ro te in

"gb :NM_025205 .1 /DEF=Homo sap iens hypo the t i ca l p ro te in DKFZp434N185 (DKFZP434N185) , mRNA. /FEA=mRNA /GEN=DKFZP434N185 /PROD=hypo the t i ca l p ro te in DKFZp434N185 /DB_XREF=g i :13376801 /UG=Hs .33032 hypo the t i ca l p ro te in DKFZp434N185 /FL=gb :AF31768 .

"gb:NM_004175.1 /DEF=Homo sapiens small nuclear r ibonucleoprotein D3 polypeptide (18kD) (SNRPD3), mRNA. /FEA=mRNA /GEN=SNRPD3 /PROD=small nuclear r ibonucleoprotein D3 polypeptide(18kD) /DB_XREF=gi:4759159 /UG=Hs.1575 small nuclear r ibonucleoprotein D.

"gb:AF309553.1 /DEF=Homo sapiens meiot ic recombinat ion protein REC14 mRNA, complete cds. /FEA=mRNA /PROD=meiot ic recombinat ion protein REC14 /DB_XREF=gi :11139241 /UG=Hs.296242 recombinat ion protein REC14 /FL=gb:AF309553.1 gb:NM_025234.1"

"gb:AF081496.1 /DEF=Homo sapiens kinetochore protein BUB3 (BUB3) mRNA, complete cds. /FEA=mRNA /GEN=BUB3 /PROD=kinetochore protein BUB3 /DB_XREF=gi:3639059 /UG=Hs.40323 BUB3 (budding uninhibi ted by benzimidazoles 3, yeast) homolog /FL=gb:BC005138.1 gb.

C o n s e n s u s i n c l u d e s g b : A I 3 0 2 2 6 2 / F E A = E S T / D B _ X R E F = g i : 3 9 6 1 6 0 8 / D B _ X R E F = e s t : q o 1 7 c 0 6 . x 1 / C L O N E = I M A G E : 1 9 0 8 7 7 8 / U G = H s . 1 0 9 3 9 0 E S T s

"gb:NM_006578.1 /DEF=Homo sapiens guanine nucleotide binding protein (G protein), beta 5 (GNB5), mRNA. /FEA=mRNA /GEN=GNB5 /PROD=guanine nucleotide binding protein (G protein),beta 5 /DB_XREF=gi:5729851 /UG=Hs.275353 guanine nucleotide binding protein (G prote.

"Consensus inc ludes gb :BF110217 /FEA=EST /DB_XREF=g i :10939907 /DB_XREF=es t :7n51a09 .x1 /CLONE=IMAGE:3568025 /UG=Hs.270621 ESTs , Modera te ly s im i la r to Pro -Po l -dUTPase po lyp ro te in M.muscu lus "

"gb:NM_005982.1 /DEF=Homo sapiens sine ocul is homeobox (Drosophi la) homolog 1 (SIX1), mRNA. /FEA=mRNA /GEN=SIX1 /PROD=sine ocul is homeobox (Drosophi la) homolog 1 /DB_XREF=gi:5174680 /UG=Hs.54416 sine ocul is homeobox (Drosophi la) homolog 1 /FL=gb:NM_.

"Consensus inc ludes gb:AI753038 /FEA=EST /DB_XREF=gi :5131302 /DB_XREF=est :cr04b07.x2 /CLONE=HBMSC_cr04b07 /UG=Hs.205274 ESTs, Weakly s imi lar to S47072 f inger pro te in HZF10, Krueppel - re la ted H.sapiens"

"gb:AF125373.1 /DEF=Homo sap iens enamel in mRNA, complete cds. /FEA=mRNA /PROD=enamel in /DB_XREF=gi :12002215 /UG=Hs.283949 Homo sap iens enamel in mRNA, complete cds /FL=gb:AF125373.1"

C o n s e n s u s i n c l u d e s g b : A W 0 2 8 5 2 1 / F E A = E S T / D B _ X R E F = g i : 5 8 8 7 2 7 7 / D B _ X R E F = e s t : w v 2 7 e 0 9 . x 1 / C L O N E = I M A G E : 2 5 3 0 7 9 2 / U G = H s . 2 3 3 7 8 5 E S T s

C o n s e n s u s i n c l u d e s g b : A W 0 2 5 1 4 1 / F E A = E S T / D B _ X R E F = g i : 5 8 7 8 6 7 1 / D B _ X R E F = e s t : w u 9 4 d 0 5 . x 1 / C L O N E = I M A G E : 2 5 2 7 6 8 9 / U G = H s . 2 7 1 9 6 E S T s

C o n s e n s u s i n c l u d e s g b : A W 3 4 0 0 9 3 / F E A = E S T / D B _ X R E F = g i : 6 8 3 6 7 1 9 / D B _ X R E F = e s t : h c 9 3 b 1 1 . x 1 / C L O N E = I M A G E : 2 9 0 7 5 4 9 / U G = H s . 1 3 0 5 3 8 E S T s

Fc alpha receptor

Programmed cell death 10

N-ras

Hsp 27

Hrk activator of apoptosis

Ubiquitin carrier protein

response non-response

Cancer/testis antigen 2

0

20

40

60

80

100

120

0 5PS-341(nM)

% c

on

tro

l

**

0

20

40

60

80

100

120

0 20 40

% c

on

tro

l

PS-341 (nM)

**

**

p38 MAPK

MAP kinase-activated protein kinase-2

(MAPKAPK-2)

Hsp27

SCIO-469

0100200

SCIO-469 (nM)

MM.1S

Pat cells (PS-341 resistant)

p38 MAPK Inhibitor (SCIO-469) Enhances Bortezomib-Induced Cytotoxicity

Hideshima et al. Oncogene 2004; in press

Conclusions

1. A new treatment paradigm targeting both thetumor cell and its microenvironment canovercome drug resistance.

2. Ongoing oncogenomic and proteomic studiesare defining novel targets governing tumor celland host interactions as well as informingclinical protocol design.