Oncogenomics to Target the Tumor Cell in its Microenvironment
Transcript of Oncogenomics to Target the Tumor Cell in its Microenvironment
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.