Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents

Abstract
Biomarkers that are useful for identifying a mammal that will respond therapeutically or is responding therapeutically to a method of treating cancer that comprises administering a microtubule-stabilizing agent. In one aspect, the cancer is breast cancer, and the microtubule-stabilizing agent is an epothilone or analog or derivative thereof, or ixabepilone.
Description
SEQUENCE LISTING

A compact disc labeled “Copy 1” contains the Sequence Listing as 10338 NP.ST25.txt. The Sequence Listing is 1686 KB in size and was recorded Nov. 29, 2005. The compact disk is 1 of 2 compact disks. A duplicate copy of the compact disc is labeled “Copy 2” and is 2 of 2 compact discs.


The compact disc and duplicate copy are identical and are hereby incorporated by reference into the present application.


FIELD OF THE INVENTION

The present invention relates generally to the field of pharmacogenomics, and more specifically to methods and procedures to determine drug sensitivity in patients to allow the identification of individualized genetic profiles which will aid in treating diseases and disorders.


BACKGROUND OF THE INVENTION

Cancer is a disease with extensive histoclinical heterogeneity. Although conventional histological and clinical features have been correlated to prognosis, the same apparent prognostic type of tumors varies widely in its responsiveness to therapy and consequent survival of the patient.


New prognostic and predictive markers, which would facilitate an individualization of therapy for each patient, are needed to accurately predict patient response to treatments, such as small molecule or biological molecule drugs, in the clinic. The problem may be solved by the identification of new parameters that could better predict the patient's sensitivity to treatment. The classification of patient samples is a crucial aspect of cancer diagnosis and treatment. The association of a patient's response to a treatment with molecular and genetic markers can open up new opportunities for treatment development in non-responding patients, or distinguish a treatment's indication among other treatment choices because of higher confidence in the efficacy. Further, the pre-selection of patients who are likely to respond well to a medicine, drug, or combination therapy may reduce the number of patients needed in a clinical study or accelerate the time needed to complete a clinical development program (M. Cockett et al., Current Opinion in Biotechnology, 11:602-609 (2000)).


The ability to predict drug sensitivity in patients is particularly challenging because drug responses reflect not only properties intrinsic to the target cells, but also a host's metabolic properties. Efforts to use genetic information to predict drug sensitivity have primarily focused on individual genes that have broad effects, such as the multidrug resistance genes, mdr1 and mrp1 (P. Sonneveld, J. Intern. Med., 247:521-534 (2000)).


The development of microarray technologies for large scale characterization of gene mRNA expression pattern has made it possible to systematically search for molecular markers and to categorize cancers into distinct subgroups not evident by traditional histopathological methods (J. Khan et al., Cancer Res., 58:5009-5013 (1998); A. A. Alizadeh et al., Nature, 403:503-511 (2000); M. Bittner et al., Nature, 406:536-540 (2000); J. Khan et al., Nature Medicine, 7(6):673-679 (2001); T. R. Golub et al., Science, 286:531-537 (1999); U. Alon et al., P. N. A. S. USA, 96:6745-6750 (1999)). Such technologies and molecular tools have made it possible to monitor the expression level of a large number of transcripts within a cell population at any given time (see, e.g., Schena et al., Science, 270:467-470 (1995); Lockhart et al., Nature Biotechnology, 14:1675-1680 (1996); Blanchard et al., Nature Biotechnology, 14:1649 (1996); U.S. Pat. No. 5,569,588 to Ashby et al.).


Recent studies demonstrate that gene expression information generated by microarray analysis of human tumors can predict clinical outcome (L. J. van't Veer et al., Nature, 415:530-536 (2002); T. Sorlie et al., P. N. A. S. USA, 98:10869-10874 (2001); M. Shipp et al., Nature Medicine, 8(1):68-74 (2002); G. Glinsky et al., The Journal of Clin. Invest., 113(6):913-923 (2004)). These findings bring hope that cancer treatment will be vastly improved by better predicting the response of individual tumors to therapy.


Needed are new and alternative methods and procedures to determine drug sensitivity in patients to allow the development of individualized genetic profiles which are necessary to treat diseases and disorders based on patient response at a molecular level.


SUMMARY OF THE INVENTION

The invention provides methods and procedures for determining patient sensitivity to one or more microtubule-stabilizing agents. The invention also provides methods of determining or predicting whether an individual requiring therapy for a disease state such as cancer will or will not respond to treatment, prior to administration of the treatment, wherein the treatment comprises administration of one or more microtubule-stabilizing agents.


In one aspect, the invention provides a method for identifying a mammal that will respond therapeutically to a method of treating cancer comprising administering a microtubule-stabilizing agent, wherein the method comprises: (a) measuring in the mammal the level of at least one biomarker selected from the biomarkers of Table 1 and Table 2; (b) exposing a biological sample from the mammal to the agent; (c) following the exposing in step (b), measuring in said biological sample the level of the at least one biomarker, wherein an increase in the level of the at least one biomarker measured in step (c) compared to the level of the at least one biomarker measured in step (a), predicts that the mammal will respond therapeutically to said method of treating cancer when said biomarker is from Table 1, and predicts that the mammal will not respond therapeutically to said method of treating cancer when said biomarker is from Table 2.


In another aspect, the invention provides a method for determining whether a mammal is responding therapeutically to a microtubule-stabilizing agent, comprising (a) exposing the mammal to the agent; and (b) following the exposing of step (a), measuring in the mammal the level of at least one biomarker selected from the biomarkers of Table 1 and Table 2, wherein an increase in the level of the at least one biomarker measured in step (b), compared to the level of the at least one biomarker in a mammal that has not been exposed to said agent, indicates that the mammal is responding to said agent when said biomarker is from Table 1, and indicates that the mammal is not responding to said agent when said biomarker is from Table 2.


In another aspect, the invention provides a method for predicting whether a mammal will respond therapeutically to a method of treating cancer comprising administering a microtubule-stabilizing agent, wherein the method comprises: (a) exposing a biological sample from the mammal to the microtubule-stabilizing agent; (b) following the exposing of step (a), measuring in said biological sample the level of at least one biomarker selected from the biomarkers of Table 1 or Table 2, wherein an increase in the level of the at least one biomarker measured in step (b), compared to the level of the at least one biomarker in a mammal that has not been exposed to said agent, predicts that the mammal will respond therapeutically to said method of treating cancer when said biomarker is from Table 1, and predicts that the mammal will not respond therapeutically to said method of treating cancer when said biomarker is from Table 2.


In another aspect, the invention provides a method for determining whether an agent stabilizes microtubules and has cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease in a mammal, comprising: (a) exposing the mammal to the agent; and (b) following the exposing of step (a), measuring in the mammal the level of at least one biomarker selected from the biomarkers of Table 1 and Table 2, wherein an increase in the level of said at least one biomarker measured in step (b), compared to the level of the biomarker in a mammal that has not been exposed to said agent, indicates that the agent stabilizes microtubules and has cytotoxic activity against rapidly proliferating cells when said biomarker is from Table 1, and indicates that the agent does not stabilize microtubules and does not have cytotoxic activity against rapidly proliferating cells when said biomarker is from Table 2.


As used herein, respond therapeutically refers to the alleviation or abrogation of the cancer. This means that the life expectancy of an individual affected with the cancer will be increased or that one or more of the symptoms of the cancer will be reduced or ameliorated. The term encompasses a reduction in cancerous cell growth or tumor volume. Whether a mammal responds therapeutically can be measured by many methods well known in the art, such as PET imaging.


The amount of increase in the level of the at least one biomarker measured in the practice of the invention can be readily determined by one skilled in the art. In one aspect, the increase in the level of a biomarker is at least a two-fold difference, at least a three-fold difference, or at least a four-fold difference in the level of the biomarker.


The mammal can be, for example, a human, rat, mouse, dog, rabbit, pig sheep, cow, horse, cat, primate, or monkey.


The method of the invention can be, for example, an in vitro method wherein the step of measuring in the mammal the level of at least one biomarker comprises taking a biological sample from the mammal and then measuring the level of the biomarker(s) in the biological sample. The biological sample can comprise, for example, at least one of whole fresh blood, peripheral blood mononuclear cells, frozen whole blood, fresh plasma, frozen plasma, urine, saliva, skin, hair follicle, bone marrow, or tumor tissue.


The level of the at least one biomarker can be, for example, the level of protein and/or mRNA transcript of the biomarker(s).


The invention also provides an isolated biomarker selected from the biomarkers of Table 1 and Table 2. The biomarkers of the invention comprise sequences selected from the nucleotide and amino acid sequences provided in Table 1 and Table 2 and the Sequence Listing, as well as fragments and variants thereof.


The invention also provides a biomarker set comprising two or more biomarkers selected from the biomarkers of Table 1 and Table 2.


The invention also provides kits for determining or predicting whether a patient would be susceptible or resistant to a treatment that comprises one or more microtubule-stabilizing agents. The patient may have a cancer or tumor such as, for example, a breast cancer or tumor.


In one aspect, the kit comprises a suitable container that comprises one or more specialized microarrays of the invention, one or more microtubule-stabilizing agents for use in testing cells from patient tissue specimens or patient samples, and instructions for use. The kit may further comprise reagents or materials for monitoring the expression of a biomarker set at the level of mRNA or protein.


In another aspect, the invention provides a kit comprising two or more biomarkers selected from the biomarkers of Table 1 and Table 2.


In yet another aspect, the invention provides a kit comprising at least one of an antibody and a nucleic acid for detecting the presence of at least one of the biomarkers selected from the biomarkers of Table 1 and Table 2. In one aspect, the kit further comprises instructions for determining whether or not a mammal will respond therapeutically to a method of treating cancer comprising administering a microtubule-stabilizing agent. In another aspect, the instructions comprise the steps of (a) measuring in the mammal the level of at least one biomarker selected from the biomarkers of Table 1 and Table 2, (b) exposing the mammal to the microtubule-stabilizing agent, (c) following the exposing of step (b), measuring in the mammal the level of the at least one biomarker, wherein a difference in the level of the at least one biomarker measured in step (c) compared to the level of the at least one biomarker measured in step (a) predicts that the mammal will respond therapeutically to said method of treating cancer when said biomarker is from Table 1, and predicts that the mammal will not respond therapeutically to said method of treating cancer when said biomarker is from Table 2.


The invention also provides screening assays for determining if a patient will be susceptible or resistant to treatment with one or more microtubule-stabilizing agents.


The invention also provides a method of monitoring the treatment of a patient having a disease, wherein said disease is treated by a method comprising administering one or more microtubule-stabilizing agents.


The invention also provides individualized genetic profiles which are necessary to treat diseases and disorders based on patient response at a molecular level.


The invention also provides specialized microarrays, e.g., oligonucleotide microarrays or cDNA microarrays, comprising one or more biomarkers having expression profiles that correlate with either sensitivity or resistance to one or more microtubule-stabilizing agents.


The invention also provides antibodies, including polyclonal or monoclonal, directed against one or more biomarkers of the invention.


The invention will be better understood upon a reading of the detailed description of the invention when considered in connection with the accompanying figures.





BRIEF DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.



FIG. 1 illustrates classification of breast cancer cell lines based on IC50 values measured against ixabepilone treatment. The cell lines were normalized based on a mean of the log(IC50) values (a dotted line) and divided into two groups defined as sensitive or resistant. The cell lines on the left are defined as sensitive since they are below the mean of the log(IC50)s, and those on the right are defined as resistant since they are above the mean.



FIG. 2 illustrates the error rates generated from each classifier identified. From the GeneCluster analysis, classifiers containing up to 250 genes were determined. Each predictor identified was evaluated with the error rate calculated through the leave-one out cross validation. As shown in FIG. 2, error rates for classifiers (8-250 genes) remain to be the minimum at zero.



FIG. 3 illustrates the error rate calculation on random permutation. Error rates generated from several examples of random classification (random 1-11) using the software GeneCluster are plotted against the predictor sets containing up to 250 genes. As shown in the plot, the error rate calculated based on the IC50-based classification is significantly lower than the error rates based on the random classification.



FIG. 4 illustrates the top 50 genes correlated with sensitivity for ixabepilone. The red and blue matrix represents the normalized expression patterns for each gene across the cell lines (brightest red indicates highest relative expression, darkest blue indicates lowest relative expression).



FIG. 5 illustrates gene expression level of microtubule associated protein, tau and estrogen receptor (also referred to herein as estrogen receptor 1, ER, and ER1). In order to explore the relationship between Tau and ER, gene expression levels of the two are plotted for each cell line. Tau expression levels are shown as a bar, and ER as a line.



FIG. 6 illustrates gene expression patterns of top 50 genes in 175 primary breast tumors. The red and green matrix represents the normalized expression patterns for each gene across the 175 primary breast tumors (brightest red indicates highest relative expression, green indicates lowest relative expression). A subset of tumors in a blue box shows relative high expression of the top 25 markers which expressed highly in the sensitive cell lines. On the other hand, the tumors in a magenta box show relatively high expression of the 25 genes expressed at elevated levels in the resistant cell lines.



FIG. 7 illustrates MAP tau and ER expression in breast tumors. In order to see the expression patterns of Tau and ER within tumors, their expression levels are plotted together. Tau is shown as a line, and ER as a bar. Tumors are arranged in an increasing order of Tau expression level. There seems to be a subset of tumors that express these genes highly, which suggest these are non-responders for ixabepilone.



FIG. 8 illustrates the biological networks implied in the mechanism of resistance to ixabepilone as determined by Ingenuity® pathway analysis using 200 preclinical candidate markers. There are nine major networks indicated above with their significance scores. As shown, ER pathway is the most implicated network.



FIG. 9 illustrates the most implicated ER network and shows the functional connectivity between ER and Tau.



FIG. 10 illustrates molecular intrinsic profiles of 134 patient tumors. A hierarchical clustering analysis was performed using about 9800 genes after eliminating low expressed and low variance genes. Row, gene; column, tumor. The tumors were classified into two major clusters and, interestingly, the majority of the samples from three Russian sites were clustered in the first cluster.





DETAILED DESCRIPTION OF THE INVENTION

The invention provides biomarkers that correlate with microtubule-stabilization agent sensitivity or resistance. These biomarkers can be employed for predicting response to one or more microtubule-stabilization agents. In one aspect, the biomarkers of the invention are those provided in Table 1, Table 2, and the Sequence Listing, including both polynucleotide and polypeptide sequences.


The biomarkers provided in Table 1 include the nucleotide sequences of SEQ ID NOS:1-100 and the amino acid sequences of SEQ ID NOS:201-299.









TABLE 1







BIOMARKERS (SENSITIVE)












Affymetrix



Unigene title and

Probe
Gene


SEQ ID NO:
Affymetrix Description
Set
Ontology





C6orf145:
“Consensus includes gb: AK024828.1
212923_s_at



chromosome 6
/DEF = Homo sapiens cDNA: FLJ21175


open reading
fis, clone CAS11071. /FEA = mRNA


frame 145
/DB_XREF = gi: 10437233


(LOC221749)
/UG = Hs.69388 hypothetical protein


SEQ ID NOS: 1
FLJ20505”


(DNA) and 201


(amino acid)


RTCD1: RNA
“gb: NM_003729.1 /DEF = Homo sapiens
203594_at
assembly


terminal phosphate
RNA 3-terminal phosphate cyclase

of


cyclase domain 1
(RPC), mRNA. /FEA = mRNA

spliceosomal


(LOC8634)
/GEN = RPC /PROD = RNA 3-terminal

tri-


SEQ ID NOS: 2
phosphate cyclase

snRNP


(DNA) and 202
/DB_XREF = gi: 4506588 /UG = Hs.27076


(amino acid)
RNA 3-terminal phosphate cyclase



/FL = gb: NM_003729.1”


FXYD5: FXYD
“gb: NM_014164.2 /DEF = Homo sapiens
218084_x_at
negative


domain containing
FXYD domain-containing ion transport

regulation


ion transport
regulator 5 (FXYD5), mRNA.

of


regulator 5
/FEA = mRNA /GEN = FXYD5

calcium-


(LOC53827)
/PROD = related to ion channel

dependent


SEQ ID NOS: 3
/DB_XREF = gi: 11612664

cell-cell


(DNA) and 203
/UG = Hs.294135 FXYD domain-

adhesion


(amino acid)
containing ion transport regulator 5



/FL = gb: NM_014164.2 gb: AF161462.1”


G3BP: Ras-
Consensus includes gb: BG500067
201503_at
protein-


GTPase-activating
/FEA = EST /DB_XREF = gi: 13461584

nucleus


protein SH3-
/DB_XREF = est: 602545874F1

import


domain-binding
/CLONE = IMAGE: 4668234


protein
/UG = Hs.220689 Ras-GTPase-activating


(LOC10146)
protein SH3-domain-binding protein


SEQ ID NOS: 4
/FL = gb: U32519.1 gb: NM_005754.1


(DNA) and 204


(amino acid)


FKBP1A: FK506
“gb: NM_000801.1 /DEF = Homo sapiens
200709_at
protein


binding protein
FK506-binding protein 1A (12 kD)

folding


1A, 12 kDa
(FKBP1A), mRNA. /FEA = mRNA


(LOC2280)
/GEN = FKBP1A /PROD = FK506-binding


SEQ ID NOS: 5
protein 1A (12 kD)


(DNA) and 205
/DB_XREF = gi: 4503724 /UG = Hs.752


(amino acid)
FK506-binding protein 1A (12 kD)



/FL = gb: BC001925.1 gb: M34539.1



gb: NM_000801.1”


VARS2: valyl-
“gb: NM_006295.1 /DEF = Homo sapiens
201797_s_at
translational


tRNA synthetase 2
valyl-tRNA synthetase 2 (VARS2),

elongation


(LOC7407)
mRNA. /FEA = mRNA /GEN = VARS2


SEQ ID NOS: 6
/PROD = valyl-tRNA synthetase 2


(DNA) and 206
/DB_XREF = gi: 5454157


(amino acid)
/UG = Hs.159637 valyl-tRNA synthetase



2 /FL = gb: NM_006295.1”


FKBP1A: FK506
Consensus includes gb: AI936769
214119_s_at
protein


binding protein
/FEA = EST /DB_XREF = gi: 5675639

folding


1A, 12 kDa
/DB_XREF = est: wp69c11.x1


(LOC2280)
/CLONE = IMAGE: 2467028 /UG = Hs.752


SEQ ID NOS: 7
FK506-binding protein 1A (12 kD)


(DNA) and 207


(amino acid)


MTMR2:
“Consensus includes gb: AK027038.1
203211_s_at
protein


myotubularin
/DEF = Homo sapiens cDNA: FLJ23385

amino


related protein 2
fis, clone HEP16802. /FEA = mRNA

acid


(LOC8898)
/DB_XREF = gi: 10440053

dephosphorylation


SEQ ID NOS: 8
/UG = Hs.181326 KIAA1073 protein


(DNA) and 208
/FL = gb: AB028996.1 gb: NM_016156.1”


(amino acid)


PSMB8:
“gb: U17496.1 /DEF = Human proteasome
209040_s_at
proteolysis


proteasome
subunit LMP7 (allele LMP7B) mRNA,

and


(prosome,
complete cds. /FEA = mRNA

peptidolysis,


macropain)
/GEN = LMP7 /PROD = proteasome

ubiquitin-


subunit, beta type,
subunit LMP7 /DB_XREF = gi: 596139

dependent


8 (large
/UG = Hs.180062 proteasome (prosome,

protein


multifunctional
macropain) subunit, beta type, 8 (large

catabolism


protease 7)
multifunctional protease 7)


(LOC5696)
/FL = gb: U17496.1 gb: U17497.1”


SEQ ID NOS: 9


(DNA) and 209


(amino acid)


CTSC: cathepsin C
“gb: NM_001814.1 /DEF = Homo sapiens
201487_at
proteolysis


(LOC1075)
cathepsin C (CTSC), mRNA.

and


SEQ ID NOS: 10
/FEA = mRNA /GEN = CTSC

peptidolysis


(DNA) and 210
/PROD = cathepsin C


(amino acid)
/DB_XREF = gi: 4503140 /UG = Hs.10029



cathepsin C /FL = gb: NM_001814.1”


ST5: suppression
“gb: NM_005418.1 /DEF = Homo sapiens
202440_s_at


of tumorigenicity 5
suppression of tumorigenicity 5 (ST5),


(LOC6764)
mRNA. /FEA = mRNA /GEN = ST5


SEQ ID NOS: 11
/PROD = suppression of tumorigenicity 5


(DNA) and 211
/DB_XREF = gi: 4885612 /UG = Hs.79265


(amino acid)
suppression of tumorigenicity 5



/FL = gb: U15131.1 gb: U15779.1



gb: NM_005418.1”


MTMR2:
“Consensus includes gb: U58033.1
214649_s_at
protein


myotubularin
/DEF = Homo sapiens myotubularin

amino


related protein 2
related protein 2 (MTMR2) mRNA,

acid


(LOC8898)
partial cds. /FEA = mRNA

dephosphorylation


SEQ ID NOS: 12
/GEN = MTMR2 /PROD = myotubularin


(DNA) and 212
related protein 2 /DB_XREF = gi: 3912941


(amino acid)
/UG = Hs.278491 myotubularin related



protein 2 /FL = gb: NM_003912.1”


PRNP: prion
“gb: NM_000311.1 /DEF = Homo sapiens
201300_s_at


protein (p27-30)
prion protein (p27-30) (Creutzfeld-Jakob


(Creutzfeld-Jakob
disease, Gerstmann-Strausler-Scheinker


disease,
syndrome, fatal familial insomnia)


Gerstmann-
(PRNP), mRNA. /FEA = mRNA


Strausler-
/GEN = PRNP /PROD = prion protein


Scheinker
/DB_XREF = gi: 4506112 /UG = Hs.74621


syndrome, fatal
prion protein (p27-30) (Creutzfeld-Jakob


familial insomnia)
disease, Gerstmann-Strausler-Scheinker


(LOC5621)
syndrome, fatal familial insomnia)


SEQ ID NOS: 13
/FL = gb: AY008282.1 gb: M13899.1


(DNA) and 213
gb: NM_000311.1”


(amino acid)


MET: met proto-
“gb: U19348.1 /DEF = Human (tpr-met
211599_x_at
signal


oncogene
fusion) oncogene mRNA, complete cds.

transduction


(hepatocyte
/FEA = mRNA /GEN = tprmet fusion


growth factor
/PROD = tpr-met fusion protein


receptor)
/DB_XREF = gi: 625085


(LOC4233)
/FL = gb: U19348.1”


SEQ ID NOS: 14


(DNA) and 214


(amino acid)


MIRAB13:
“Cluster Incl. W46406: zc31c10.s1 Homo
55081_at
vesicle-


molecule

sapiens cDNA, 3 end /clone = IMAGE-


mediated


interacting with
323922 /clone_end = 3′ /gb = W46406

transport


Rab13
/gi = 1331036 /ug = Hs.8535 /len = 568”


(LOC85377)


SEQ ID NOS: 15


(DNA) and 215


(amino acid)


AKAP2: A kinase
Consensus includes gb: BE879367
202759_s_at


(PRKA) anchor
/FEA = EST /DB_XREF = gi: 10328143


protein 2
/DB_XREF = est: 601484628F1


(LOC11217)
/CLONE = IMAGE: 3887262


SEQ ID NOS: 16
/UG = Hs.42322 A kinase (PRKA) anchor


(DNA) and 216
protein 2 /FL = gb: AB023137.1


(amino acid)
gb: NM_007203.1


MET: met proto-
Consensus includes gb: BG170541
203510_at
signal


oncogene
/FEA = EST /DB_XREF = gi: 12677244

transduction


(hepatocyte
/DB_XREF = est: 602322942F1


growth factor
/CLONE = IMAGE: 4425947


receptor)
/UG = Hs.285754 met proto-oncogene


(LOC4233)
(hepatocyte growth factor receptor)


SEQ ID NOS: 17
/FL = gb: J02958.1 gb: NM_000245.1


(DNA) and 217


(amino acid)


STAC: SH3 and
“gb: NM_003149.1 /DEF = Homo sapiens
205743_at
intracellular


cysteine rich
src homology three (SH3) and cysteine

signaling


domain
rich domain (STAC), mRNA.

cascade


(LOC6769)
/FEA = mRNA /GEN = STAC /PROD = src


SEQ ID NOS: 18
homology three (SH3) and cysteine


(DNA) and 218
richdomain /DB_XREF = gi: 4507246


(amino acid)
/UG = Hs.56045 src homology three



(SH3) and cysteine rich domain



/FL = gb: D86640.1 gb: NM_003149.1”


CALU: calumenin
Consensus includes gb: BF939365
200755_s_at


(LOC813)
/FEA = EST /DB_XREF = gi: 12356685


SEQ ID NOS: 19
/DB_XREF = est: nad87h04.x1


(DNA) and 219
/CLONE = IMAGE: 3410551


(amino acid)
/UG = Hs.7753 calumenin



/FL = gb: U67280.1 gb: AF013759.1



gb: NM_001219.2


MSN: moesin
“gb: NM_002444.1 /DEF = Homo sapiens
200600_at
cell


(LOC4478)
moesin (MSN), mRNA. /FEA = mRNA

motility


SEQ ID NOS: 20
/GEN = MSN /PROD = moesin


(DNA) and 220
/DB_XREF = gi: 4505256


(amino acid)
/UG = Hs.170328 moesin



/FL = gb: M69066.1 gb: NM_002444.1”


ANXA1: annexin
“gb: NM_000700.1 /DEF = Homo sapiens
201012_at
inflammatory


A1 (LOC301)
annexin A1 (ANXA1), mRNA.

response,


SEQ ID NOS: 21
/FEA = mRNA /GEN = ANXA1

cell


(DNA) and 221
/PROD = annexin I

motility


(amino acid)
/DB_XREF = gi: 4502100 /UG = Hs.78225



annexin A1 /FL = gb: BC001275.1



gb: NM_000700.1”


CGI-100: CGI-100
“gb: NM_016040.1 /DEF = Homo sapiens
202195_s_at
intracellular


protein
CGI-100 protein (LOC50999), mRNA.

protein


(LOC50999)
/FEA = mRNA /GEN = LOC50999

transport


SEQ ID NOS: 22
/PROD = CGI-100 protein


(DNA) and 222
/DB_XREF = gi: 7705583


(amino acid)
/UG = Hs.296155 CGI-100 protein



/FL = gb: AF151858.1 gb: NM_016040.1”


CALU: calumenin
“gb: NM_001219.2 /DEF = Homo sapiens
200757_s_at


(LOC813)
calumenin (CALU), mRNA.


SEQ ID NOS: 23
/FEA = mRNA /GEN = CALU


(DNA) and 223
/PROD = calumenin precursor


(amino acid)
/DB_XREF = gi: 6005991 /UG = Hs.7753



calumenin /FL = gb: U67280.1



gb: AF013759.1 gb: NM_001219.2”


EGFR: epidermal
“gb: U95089.1 /DEF = Human truncated
210984_x_at
EGF


growth factor
epidermal growth factor receptor-like

receptor


receptor
protein precursor mRNA, complete cds.

signaling


(erythroblastic
/FEA = mRNA /PROD = truncated

pathway


leukemia viral (v-
epidermal growth factor receptor-


erb-b) oncogene
likeprotein precursor


homolog, avian)
/DB_XREF = gi: 2051984 /UG = Hs.77432


(LOC1956)
epidermal growth factor receptor (avian


SEQ ID NOS: 24
erythroblastic leukemia viral (v-erb-b)


(DNA) and 224
oncogene homolog) /FL = gb: U95089.1”


(amino acid)


CASP4: caspase 4,
“gb: U25804.1 /DEF = Human Ich-2
209310_s_at
apoptosis


apoptosis-related
cysteine protease mRNA, complete cds.


cysteine protease
/FEA = mRNA /PROD = Ich-2


(LOC837)
/DB_XREF = gi: 886049 /UG = Hs.74122


SEQ ID NOS: 25
caspase 4, apoptosis-related cysteine


(DNA) and 225
protease /FL = gb: U28976.1 gb: U28977.1


(amino acid)
gb: U28978.1 gb: NM_001225.1



gb: U25804.1 gb: U28014.1”


DKFZP566E144:
“gb: NM_015523.1 /DEF = Homo sapiens
218194_at
nucleotide


small fragment
small fragment nuclease

metabolism


nuclease
(DKFZP566E144), mRNA.


(LOC25996)
/FEA = mRNA /GEN = DKFZP566E144


SEQ ID NOS: 26
/PROD = small fragment nuclease


(DNA) and 226
/DB_XREF = gi: 7661645 /UG = Hs.7527


(amino acid)
small fragment nuclease



/FL = gb: AF151872.1 gb: AL110239.1



gb: NM_015523.1”


AKR1B1: aldo-
“gb: NM_001628.1 /DEF = Homo sapiens
201272_at
carbohydrate


keto reductase
aldo-keto reductase family 1, member B1

metabolism


family 1, member
(aldose reductase) (AKR1B1), mRNA.


B1 (aldose
/FEA = mRNA /GEN = AKR1B1


reductase)
/PROD = aldo-keto reductase family 1,


(LOC231)
member B1 (aldosereductase)


SEQ ID NOS: 27
/DB_XREF = gi: 4502048 /UG = Hs.75313


(DNA) and 227
aldo-keto reductase family 1, member B1


(amino acid)
(aldose reductase) /FL = gb: BC000260.1



gb: BC005387.1 gb: J04795.1 gb: J05017.1



gb: J05474.1 gb: M34720.1



gb: NM_001628.1”


CAV1: caveolin 1,
Consensus includes gb: AU147399
212097_at


caveolae protein,
/FEA = EST /DB_XREF = gi: 11008920


22 kDa (LOC857)
/DB_XREF = est: AU147399


SEQ ID NOS: 28
/CLONE = MAMMA1000563


(DNA) and 228
/UG = Hs.74034 Homo sapiens clone


(amino acid)
24651 mRNA sequence


MBNL2:
Consensus includes gb: BE328496
203640_at


muscleblind-like 2
/FEA = EST /DB_XREF = gi: 9202272


(Drosophila)
/DB_XREF = est: hs98f09.x1


(LOC10150)
/CLONE = IMAGE: 3145289


SEQ ID NOS: 29
/UG = Hs.283609 hypothetical protein


(DNA) and 229
PRO2032 /FL = gb: AF116683.1


(amino acid)
gb: NM_018615.1


CRSP6: cofactor
“gb: AF105421.1 /DEF = Homo sapiens
221517_s_at
regulation


required for Sp1
vitamin D3 receptor interacting protein

of


transcriptional
(DRIP80) mRNA, complete cds.

transcription,


activation, subunit
/FEA = mRNA /GEN = DRIP80

DNA-


6, 77 kDa
/PROD = vitamin D3 receptor interacting

dependent


(LOC9440)
protein /DB_XREF = gi: 4838128


SEQ ID NOS: 30
/UG = Hs.22630 cofactor required for Sp1


(DNA) and 230
transcriptional activation, subunit 6


(amino acid)
(77 kD) /FL = gb: AF105421.1”


CALU: calumenin
“gb: U67280.1 /DEF = Homo sapiens
200756_x_at


(LOC813)
calumenin mRNA, complete cds.


SEQ ID NOS: 31
/FEA = mRNA /PROD = calumenin


(DNA) and 231
/DB_XREF = gi: 2809323 /UG = Hs.7753


(amino acid)
calumenin /FL = gb: U67280.1



gb: AF013759.1 gb: NM_001219.2”


PTRF: polymerase
“Consensus includes gb: BC004295.1
208789_at


I and transcript
/DEF = Homo sapiens, clone


release factor
IMAGE: 3622356, mRNA, partial cds.


(LOC284119)
/FEA = mRNA /PROD = Unknown


SEQ ID NOS: 32
(protein for IMAGE: 3622356)


(DNA) and 232
/DB_XREF = gi: 13279151


(amino acid)
/UG = Hs.29759 RNA POLYMERASE I



AND TRANSCRIPT RELEASE



FACTOR /FL = gb: AF312393.1”


NUP155:
“gb: NM_004298.1 /DEF = Homo sapiens
206550_s_at
nucleocytoplasmic


nucleoporin
nucleoporin 155 kD (NUP155), mRNA.

transport


155 kDa
/FEA = mRNA /GEN = NUP155


(LOC9631)
/PROD = nucleoporin 155 kD


SEQ ID NOS: 33
/DB_XREF = gi: 4758843 /UG = Hs.23255


(DNA) and 233
nucleoporin 155 kD /FL = gb: AB018334.1


(amino acid)
gb: NM_004298.1”


DONSON:
“gb: AF232674.1 /DEF = Homo sapiens
221677_s_at


downstream
B17 mRNA, complete cds. /FEA = mRNA


neighbor of SON
/PROD = B17 /DB_XREF = gi: 8118230


(LOC29980)
/UG = Hs.17834 downstream neighbor of


SEQ ID NOS: 34
SON /FL = gb: AF232674.1”


(DNA) and 234


(amino acid)


CALU: calumenin
“Consensus includes gb: AF257659.1
214845_s_at


(LOC813)
/DEF = Homo sapiens crocalbin-like


SEQ ID NOS: 35
protein mRNA, partial cds.


(DNA) and 235
/FEA = mRNA /PROD = crocalbin-like


(amino acid)
protein /DB_XREF = gi: 8515717



/UG = Hs.302073 Homo sapiens



crocalbin-like protein mRNA, partial



cds”


FAD104: FAD104
“gb: NM_022763.1 /DEF = Homo sapiens
218618_s_at


(LOC64778)
hypothetical protein FLJ23399


SEQ ID NOS: 36
(FLJ23399), mRNA. /FEA = mRNA


(DNA) and 236
/GEN = FLJ23399 /PROD = hypothetical


(amino acid)
protein FLJ23399



/DB_XREF = gi: 12232434



/UG = Hs.299883 hypothetical protein



FLJ23399 /FL = gb: NM_022763.1”


EPHA2: EphA2
“gb: NM_004431.1 /DEF = Homo sapiens
203499_at


(LOC1969)
EphA2 (EPHA2), mRNA. /FEA = mRNA


SEQ ID NOS: 37
/GEN = EPHA2 /PROD = EphA2


(DNA) and 237
/DB_XREF = gi: 4758277


(amino acid)
/UG = Hs.171596 EphA2



/FL = gb: M59371.1 gb: NM_004431.1”


PAK1IP1: PAK1
“gb: NM_017906.1 /DEF = Homo sapiens
218886_at


interacting protein
hypothetical protein FLJ20624


1 (LOC55003)
(FLJ20624), mRNA. /FEA = mRNA


SEQ ID NOS: 38
/GEN = FLJ20624 /PROD = hypothetical


(DNA) and 238
protein FLJ20624


(amino acid)
/DB_XREF = gi: 8923576 /UG = Hs.52256



hypothetical protein FLJ20624



/FL = gb: NM_017906.1”


CTPS: CTP
“gb: NM_001905.1 /DEF = Homo sapiens
202613_at
pyrimidine


synthase
CTP synthase (CTPS), mRNA.

nucleotide


(LOC1503)
/FEA = mRNA /GEN = CTPS

biosynthesis


SEQ ID NOS: 39
/PROD = CTP synthase


(DNA) and 239
/DB_XREF = gi: 4503132


(amino acid)
/UG = Hs.251871 CTP synthase



/FL = gb: NM_001905.1”


CD44: CD44
“gb: BC004372.1 /DEF = Homo sapiens,
209835_x_at
cell-cell


antigen (homing
Similar to CD44 antigen (homing

adhesion


function and
function and Indian blood group system),


Indian blood group
clone MGC: 10468, mRNA, complete


system) (LOC960)
cds. /FEA = mRNA /PROD = Similar to


SEQ ID NOS: 40
CD44 antigen (homing function


(DNA) and 240
andIndian blood group system)


(amino acid)
/DB_XREF = gi: 13325117



/UG = Hs.169610 CD44 antigen (homing



function and Indian blood group system)



/FL = gb: BC004372.1”


CD97: CD97
“gb: NM_001784.1 /DEF = Homo sapiens
202910_s_at
G-protein


antigen (LOC976)
CD97 antigen (CD97), mRNA.

coupled


SEQ ID NOS: 41
/FEA = mRNA /GEN = CD97

receptor


(DNA) and 241
/PROD = CD97 antigen

protein


(amino acid)
/DB_XREF = gi: 4502690./UG = Hs.3107

signaling



CD97 antigen /FL = gb: NM_001784.1”

pathway


SPTBN1: spectrin,
“Consensus includes gb: BE968833
212071_s_at


beta, non-
/FEA = EST /DB_XREF = gi: 10579538


erythrocytic 1
/DB_XREF = est: 601649861F1


(LOC6711)
/CLONE = IMAGE: 3933782


SEQ ID NOS: 42
/UG = Hs.324648 Homo sapiens cDNA


(DNA) and 242
FLJ13700 fis, clone PLACE2000216,


(amino acid)
highly similar to SPECTRIN BETA



CHAIN, BRAIN”


SH3GLB1: SH3-
“gb: AF263293.1 /DEF = Homo sapiens
209091_s_at


domain GRB2-like
endophilin B1 mRNA, complete cds.


endophilin B1
/FEA = mRNA /PROD = endophilin B1


(LOC51100)
/DB_XREF = gi: 8118529


SEQ ID NOS: 43
/UG = Hs.136309 SH3-containing protein


(DNA) and 243
SH3GLB1 /FL = gb: AF263293.1”


(amino acid)


PGM1:
“gb: NM_002633.1 /DEF = Homo sapiens
201968_s_at
glucose


phosphoglucomutase
phosphoglucomutase 1 (PGM1), mRNA.

metabolism


1 (LOC5236)
/FEA = mRNA /GEN = PGM1


SEQ ID NOS: 44
/PROD = phosphoglucomutase 1


(DNA) and 244
/DB_XREF = gi: 4505764 /UG = Hs.1869


(amino acid)
phosphoglucomutase 1



/FL = gb: BC001756.1 gb: M83088.1



gb: NM_002633.1”


SH3GLB1: SH3-
“gb: AF257318.1 /DEF = Homo sapiens
210101_x_at


domain GRB2-like
SH3-containing protein SH3GLB1


endophilin B1
mRNA, complete cds. /FEA = mRNA


(LOC51100)
/PROD = SH3-containing protein


SEQ ID NOS: 45
SH3GLB1 /DB_XREF = gi: 8896091


(DNA) and 245
/UG = Hs.136309 SH3-containing protein


(amino acid)
SH3GLB1 /FL = gb: AF350371.1



gb: AF151819.1 gb: NM_016009.1



gb: AF257318.1”


GBP1: guanylate
“gb: BC002666.1 /DEF = Homo sapiens,
202269_x_at
immune


binding protein 1,
guanylate binding protein 1, interferon-

response


interferon-
inducible, 67 kD, clone MGC: 3949,


inducible, 67 kDa
mRNA, complete cds. /FEA = mRNA


(LOC2633)
/PROD = guanylate binding protein


SEQ ID NOS: 46
1, interferon-inducible, 67 kD


(DNA) and 246
/DB_XREF = gi: 12803662


(amino acid)
/UG = Hs.62661 guanylate binding protein



1, interferon-inducible, 67 kD



/FL = gb: BC002666.1 gb: M55542.1



gb: NM_002053.1”


ADORA2B:
“gb: NM_000676.1 /DEF = Homo sapiens
205891_at
adenylate


adenosine A2b
adenosine A2b receptor (ADORA2B),

cyclase


receptor (LOC136)
mRNA. /FEA = mRNA

activation


SEQ ID NOS: 47
/GEN = ADORA2B /PROD = adenosine


(DNA) and 247
A2b receptor /DB_XREF = gi: 4501950


(amino acid)
/UG = Hs.45743 adenosine A2b receptor



/FL = gb: M97759.1 gb: NM_000676.1”


PLS3: plastin 3 (T
“gb: NM_005032.2 /DEF = Homo sapiens
201215_at


isoform)
plastin 3 (T isoform) (PLS3), mRNA.


(LOC5358)
/FEA = mRNA /GEN = PLS3


SEQ ID NOS: 48
/PROD = plastin 3 precursor


(DNA) and 248
/DB_XREF = gi: 7549808 /UG = Hs.4114


(amino acid)
plastin 3 (T isoform) /FL = gb: M22299.1



gb: NM_005032.2”


PDGFC: platelet
“gb: NM_016205.1 /DEF = Homo sapiens
218718_at


derived growth
platelet derived growth factor C


factor C
(PDGFC), mRNA. /FEA = mRNA


(LOC56034)
/GEN = PDGFC /PROD = secretory growth


SEQ ID NOS: 49
factor-like protein fallotein


(DNA) and 249
/DB_XREF = gi: 9994186 /UG = Hs.43080


(amino acid)
platelet derived growth factor C



/FL = gb: AF091434.1 gb: AF244813.1



gb: AB033831.1 gb: NM_016205.1”


MID1: midline 1
“gb: NM_000381.1 /DEF = Homo sapiens
203637_s_at
microtubule


(Opitz/BBB
midline 1 (OpitzBBB syndrome)

cytoskeleton


syndrome)
(MID1), mRNA. /FEA = mRNA

organization


(LOC4281)
/GEN = MID1 /PROD = midline 1

and


SEQ ID NOS: 50
/DB_XREF = gi: 4557752 /UG = Hs.27695

biogenesis


(DNA) and 250
midline 1 (OpitzBBB syndrome)


(amino acid)
/FL = gb: AF269101.1 gb: AF230976.1



gb: AF035360.1 gb: NM_000381.1”


MET: met proto-
Consensus includes gb: BE870509
213807_x_at
signal


oncogene
/FEA = EST /DB_XREF = gi: 10319285

transduction


(hepatocyte
/DB_XREF = est: 601447096F1


growth factor
/CLONE = IMAGE: 3851374


receptor)
/UG = Hs.285754 met proto-oncogene


(LOC4233)
(hepatocyte growth factor receptor)


SEQ ID NOS: 51


(DNA) and 251


(amino acid)


CHST6:
“gb: NM_021615.1 /DEF = Homo sapiens
221059_s_at
proteoglycan


carbohydrate (N-
carbohydrate (N-acetylglucosamine 6-O)

sulfate


acetylglucosamine
sulfotransferase 6 (CHST6), mRNA.

transfer


6-O)
/FEA = mRNA /GEN = CHST6


sulfotransferase 6
/PROD = carbohydrate (N-


(LOC4166)
acetylglucosamine 6-O)sulfotransferase 6


SEQ ID NOS: 52
/DB_XREF = gi: 11055975


(DNA) and 252
/UG = Hs.157439 carbohydrate (N-


(amino acid)
acetylglucosamine 6-O) sulfotransferase



6 /FL = gb: AF219990.1



gb: NM_021615.1”


MEIS2: Meis1,
“gb: NM_020149.1 /DEF = Homo sapiens
207480_s_at
negative


myeloid ecotropic
TALE homeobox protein Meis2e

regulation


viral integration
(LOC56908), mRNA. /FEA = mRNA

of


site 1 homolog 2
/GEN = LOC56908 /PROD = TALE

transcription


(mouse)
homeobox protein Meis2e

from


(LOC4212)
/DB_XREF = gi: 9910355

Pol II


SEQ ID NOS: 53
/UG = Hs.283312 TALE homeobox

promoter


(DNA) and 253
protein Meis2e /FL = gb: AF179899.1


(amino acid)
gb: NM_020149.1”


UPP1: uridine
“gb: NM_003364.1 /DEF = Homo sapiens
203234_at
nucleoside


phosphorylase 1
uridine phosphorylase (UP), mRNA.

metabolism


(LOC7378)
/FEA = mRNA /GEN = UP /PROD = uridine


SEQ ID NOS: 54
phosphorylase /DB_XREF = gi: 4507838


(DNA) and 254
/UG = Hs.77573 uridine phosphorylase


(amino acid)
/FL = gb: BC001405.1 gb: NM_003364.1”


CD44: CD44
Consensus includes gb: AI493245
212014_x_at
cell-cell


antigen (homing
/FEA = EST /DB_XREF = gi: 4394248

adhesion


function and
/DB_XREF = est: ti30d08.x1


Indian blood group
/CLONE = IMAGE: 2131983


system) (LOC960)
/UG = Hs.169610 CD44 antigen (homing


SEQ ID NOS: 55
function and Indian blood group system)


(DNA) and 255


(amino acid)


BTG3: BTG
“Consensus includes gb: AI765445
213134_x_at
regulation


family, member 3
/FEA = EST /DB_XREF = gi: 5231954

of cell


(LOC10950)
/DB_XREF = est: wi80b08.x1

cycle


SEQ ID NOS: 56
/CLONE = IMAGE: 2399607


(DNA) and 256
/UG = Hs.77311 BTG family, member 3”


(amino acid)


FKBP1A: FK506
“gb: BC005147.1 /DEF = Homo sapiens,
210186_s_at
protein


binding protein
FK506-binding protein 1A (12 kD), clone

folding


1A, 12 kDa
MGC: 2167, mRNA, complete cds.


(LOC2280)
/FEA = mRNA /PROD = FK506-binding


SEQ ID NOS: 57
protein 1A (12 kD)


(DNA) and 257
/DB_XREF = gi: 13477342 /UG = Hs.752


(amino acid)
FK506-binding protein 1A (12 kD)



/FL = gb: BC005147.1”


IFI16: interferon,
“gb: NM_005531.1 /DEF = Homo sapiens
206332_s_at


gamma-inducible
interferon, gamma-inducible protein 16


protein 16
(IFI16), mRNA. /FEA = mRNA


(LOC3428)
/GEN = IFI16 /PROD = interferon, gamma-


SEQ ID NOS: 58
inducible protein 16


(DNA) and 258
/DB_XREF = gi: 5031778


(amino acid)
/UG = Hs.155530 interferon, gamma-



inducible protein 16 /FL = gb: M63838.1



gb: NM_005531.1”


CD44: CD44
Consensus includes gb: BE903880
212063_at
cell-cell


antigen (homing
/FEA = EST /DB_XREF = gi: 10395551

adhesion


function and
/DB_XREF = est: 601494678F1


Indian blood group
/CLONE = IMAGE: 3896970


system) (LOC960)
/UG = Hs.323950 zinc finger protein 6


SEQ ID NOS: 59
(CMPX1)


(DNA) and 259


(amino acid)


IFI16: interferon,
“gb: AF208043.1 /DEF = Homo sapiens
208966_x_at


gamma-inducible
IFI16b (IFI16b) mRNA, complete cds.


protein 16
/FEA = mRNA /GEN = IFI16b


(LOC3428)
/PROD = IFI16b /DB_XREF = gi: 6644296


SEQ ID NOS: 60
/UG = Hs.155530 interferon, gamma-


(DNA) and 260
inducible protein 16


(amino acid)
/FL = gb: AF208043.1”


GNG12: guanine
Consensus includes gb: BG111761
212294_at
signal


nucleotide binding
/FEA = EST /DB_XREF = gi: 12605267

transduction


protein (G
/DB_XREF = est: 602285343F1


protein), gamma
/CLONE = IMAGE: 4372619


12 (LOC55970)
/UG = Hs.8107 Homo sapiens mRNA;


SEQ ID NOS: 61
cDNA DKFZp586B0918 (from clone


(DNA) and 261
DKFZp586B0918)


(amino acid)


GSTP1:
“gb: NM_000852.2 /DEF = Homo sapiens
200824_at
metabolism


glutathione S-
glutathione S-transferase pi (GSTP1),


transferase pi
mRNA. /FEA = mRNA /GEN = GSTP1


(LOC2950)
/PROD = glutathione transferase


SEQ ID NOS: 62
/DB_XREF = gi: 6552334


(DNA) and 262
/UG = Hs.226795 glutathione S-


(amino acid)
transferase pi /FL = gb: U62589.1



gb: U30897.1 gb: NM_000852.2”


MCAM:
“gb: BC006329.1 /DEF = Homo sapiens,
211042_x_at


melanoma cell
Similar to melanoma adhesion molecule,


adhesion molecule
clone MGC: 12808, mRNA, complete


(LOC4162)
cds. /FEA = mRNA /PROD = Similar to


SEQ ID NOS: 63
melanoma adhesion molecule


(DNA) and 263
/DB_XREF = gi: 13623456


(amino acid)
/FL = gb: BC006329.1”


MIRAB13:
“Consensus includes gb: BC001090.1
221779_at
vesicle-


molecule
/DEF = Homo sapiens, clone

mediated


interacting with
IMAGE: 3504989, mRNA, partial cds.

transport


Rab13
/FEA = mRNA /PROD = Unknown


(LOC85377)
(protein for IMAGE: 3504989)


SEQ ID NOS: 64
/DB_XREF = gi: 12654518 /UG = Hs.8535


(DNA) and 264
hypothetical protein bA395L14.2”


(amino acid)


IFI16: interferon,
“Consensus includes gb: BG256677
208965_s_at


gamma-inducible
/FEA = EST /DB_XREF = gi: 12766493


protein 16
/DB_XREF = est: 602370865F1


(LOC3428)
/CLONE = IMAGE: 4478872


SEQ ID NOS: 65
/UG = Hs.155530 interferon, gamma-


(DNA) and 265
inducible protein 16


(amino acid)
/FL = gb: AF208043.1”


DKFZp667G2110:
“Consensus includes gb: BE501352
214030_at


hypothetical
/FEA = EST /DB_XREF = gi: 9703760


protein
/DB_XREF = est: 7a41e05.x1


DKFZp667G2110
/CLONE = IMAGE: 3221312


(LOC131544)
/UG = Hs.23294 ESTs, Weakly similar to


SEQ ID NOS: 66
T15138 hypothetical protein T28F2.4-


(DNA)

Caenorhabditis elegans C. elegans



C1GALT1: core 1
“gb: NM_020156.1 /DEF = Homo sapiens
219439_at


UDP-galactose:N-
core1 UDP-galactose:N-


acetylgalactosamine-
acetylgalactosamine-alpha-R beta 1,3-


alpha-R beta 1,3-
galactosyltransferase (C1GALT1),


galactosyltransferase
mRNA. /FEA = mRNA


(LOC56913)
/GEN = C1GALT1 /PROD = core1UDP-


SEQ ID NOS: 67
galactose:N-acetylgalactosamine-alpha-R


(DNA) and 266
beta1,3-galactosyltransferase


(amino acid)
/DB_XREF = gi: 9910143 /UG = Hs.46744



core1 UDP-galactose:N-



acetylgalactosamine-alpha-R beta 1,3-



galactosyltransferase



/FL = gb: AF155582.1 gb: NM_020156.1”


RANGNRF: RAN
“gb: NM_014185.1 /DEF = Homo sapiens
218526_s_at


guanine nucleotide
HSPC165 protein (HSPC165), mRNA.


release factor
/FEA = mRNA /GEN = HSPC165


(LOC29098)
/PROD = HSPC165 protein


SEQ ID NOS: 68
/DB_XREF = gi: 7661825 /UG = Hs.13605


(DNA) and 267
HSPC165 protein /FL = gb: AF161514.1


(amino acid)
gb: AF151070.1 gb: NM_014185.1



gb: NM_016492.1 gb: AF168714.1



gb: AF265206.1”


ELL2: elongation
“Consensus includes gb: NM_012081.1
214446_at
regulation


factor, RNA
/DEF = Homo sapiens ELL-RELATED

of


polymerase II, 2
RNA POLYMERASE II,

transcription,


(LOC22936)
ELONGATION FACTOR (ELL2),

DNA-


SEQ ID NOS: 69
mRNA. /FEA = CDS /GEN = ELL2

dependent


(DNA) and 268
/PROD = ELL-RELATED RNA


(amino acid)
POLYMERASE II,



ELONGATIONFACTOR



/DB_XREF = gi: 6912353



/UG = Hs.173334 ELL-RELATED RNA



POLYMERASE II, ELONGATION



FACTOR /FL = gb: NM_012081.1”


BIN1: bridging
“Consensus includes gb: AF043899.1
214439_x_at
synaptic


integrator 1
/DEF = Homo sapiens amphiphysin IIc1

transmission


(LOC274)
mRNA, complete cds. /FEA = CDS


SEQ ID NOS: 70
/PROD = amphiphysin IIc1


(DNA) and 269
/DB_XREF = gi: 3064256


(amino acid)
/UG = Hs.193163 bridging integrator 1



/FL = gb: AF043899.1”


M-RIP: myosin
“Consensus includes gb: AK025604.1
214771_x_at


phosphatase-Rho
/DEF = Homo sapiens cDNA: FLJ21951


interacting protein
fis, clone HEP04968. /FEA = mRNA


(LOC23164)
/DB_XREF = gi: 10438172


SEQ ID NOS: 71
/UG = Hs.84883 KIAA0864 protein”


(DNA) and 270


(amino acid)


MGC5306:
“gb: BC001972.1 /DEF = Homo sapiens,
221580_s_at


hypothetical
clone MGC: 5306, mRNA, complete cds.


protein MGC5306
/FEA = mRNA /PROD = Unknown


(LOC79101)
(protein for MGC: 5306)


SEQ ID NOS: 72
/DB_XREF = gi: 12805036


(DNA) and 271
/UG = Hs.301732 hypothetical protein


(amino acid)
MGC5306 /FL = gb: BC001972.1”


BTN3A3:
“gb: NM_006994.2 /DEF = Homo sapiens
204820_s_at


butyrophilin,
butyrophilin, subfamily 3, member A3


subfamily 3,
(BTN3A3), mRNA. /FEA = mRNA


member A3
/GEN = BTN3A3 /PROD = butyrophilin,


(LOC10384)
subfamily 3, member A3


SEQ ID NOS: 73
/DB_XREF = gi: 6325463


(DNA) and 272
/UG = Hs.167741 butyrophilin, subfamily


(amino acid)
3, member A3 /FL = gb: U90548.1



gb: NM_006994.2”


CAV2: caveolin 2
“gb: NM_001233.1 /DEF = Homo sapiens
203324_s_at


(LOC858)
caveolin 2 (CAV2), mRNA.


SEQ ID NOS: 74
/FEA = mRNA /GEN = CAV2


(DNA) and 273
/PROD = caveolin 2


(amino acid)
/DB_XREF = gi: 4557412



/UG = Hs.139851 caveolin 2



/FL = gb: BC005256.1 gb: AF035752.1



gb: NM_001233.1”


IFNGR1:
“gb: NM_000416.1 /DEF = Homo sapiens
202727_s_at
signal


interferon gamma
interferon gamma receptor 1 (IFNGR1),

transduction


receptor 1
mRNA. /FEA = mRNA /GEN = IFNGR1


(LOC3459)
/PROD = interferon gamma receptor 1


SEQ ID NOS: 75
/DB_XREF = gi: 4557879


(DNA) and 274
/UG = Hs.180866 interferon gamma


(amino acid)
receptor 1 /FL = gb: BC005333.1



gb: J03143.1 gb: NM_000416.1”


MGC5297:
“gb: NM_024091.1 /DEF = Homo sapiens
219200_at


hypothetical
hypothetical protein MGC5297


protein MGC5297
(MGC5297), mRNA. /FEA = mRNA


(LOC79072)
/GEN = MGC5297 /PROD = hypothetical


SEQ ID NOS: 76
protein MGC5297


(DNA) and 275
/DB_XREF = gi: 13129089


(amino acid)
/UG = Hs.23856 hypothetical protein



MGC5297 /FL = gb: BC001295.1



gb: NM_024091.1”


TGFBI:
“gb: NM_000358.1 /DEF = Homo sapiens
201506_at
cell


transforming
transforming growth factor, beta-

adhesion


growth factor,
induced, 68 kD (TGFBI), mRNA.


beta-induced,
/FEA = mRNA /GEN = TGFBI


68 kDa (LOC7045)
/PROD = transforming growth factor,


SEQ ID NOS: 77
beta-induced, 68 kD


(DNA) and 276
/DB_XREF = gi: 4507466


(amino acid)
/UG = Hs.118787 transforming growth



factor, beta-induced, 68 kD



/FL = gb: BC000097.1 gb: BC004972.1



gb: M77349.1 gb: NM_000358.1”


AKAP2: A kinase
“gb: NM_007203.1 /DEF = Homo sapiens
202760_s_at


(PRKA) anchor
A kinase (PRKA) anchor protein 2


protein 2
(AKAP2), mRNA. /FEA = mRNA


(LOC11217)
/GEN = AKAP2 /PROD = A kinase


SEQ ID NOS: 78
(PRKA) anchor protein 2


(DNA) and 277
/DB_XREF = gi: 6005708 /UG = Hs.42322


(amino acid)
A kinase (PRKA) anchor protein 2



/FL = gb: AB023137.1 gb: NM_007203.1”


QKI: quaking
Consensus includes gb: AI114716
212263_at
signal


homolog, KH
/FEA = EST /DB_XREF = gi: 6360061

transduction


domain RNA
/DB_XREF = est: HA1315 /UG = Hs.15020


binding (mouse)
homolog of mouse quaking QKI (KH


(LOC9444)
domain RNA binding protein)


SEQ ID NOS: 79
/FL = gb: AF142419.1 gb: AF142422.1


(DNA) and 278


(amino acid)


PRNP: prion
“Consensus includes gb: AV725328
215707_s_at


protein (p27-30)
/FEA = EST /DB_XREF = gi: 10830606


(Creutzfeld-Jakob
/DB_XREF = est: AV725328


disease,
/CLONE = HTCAVD03 /UG = Hs.74621


Gerstmann-
prion protein (p27-30) (Creutzfeld-Jakob


Strausler-
disease, Gerstmann-Strausler-Scheinker


Scheinker
syndrome, fatal familial insomnia)”


syndrome, fatal


familial insomnia)


(LOC5621)


SEQ ID NOS: 80


(DNA) and 279


(amino acid)


HIC: I-mfa
“gb: AF054589.1 /DEF = Homo sapiens
211675_s_at


domain-containing
HIC protein isoform p40 and HIC protein


protein
isoform p32 mRNAs, complete cds.


(LOC29969)
/FEA = mRNA /PROD = HIC protein


SEQ ID NOS: 81
isoform p32; HIC protein isoform p40


(DNA) and 280
/DB_XREF = gi: 3426297


(amino acid)
/FL = gb: AF054589.1”


POPDC3: popeye
“gb: NM_022361.1 /DEF = Homo sapiens
219926_at


domain containing
popeye protein 3 (POP3), mRNA.


3 (LOC64208)
/FEA = mRNA /GEN = POP3


SEQ ID NOS: 82
/PROD = popeye protein 3


(DNA) and 281
/DB_XREF = gi: 11641280


(amino acid)
/UG = Hs.303154 popeye protein 3



/FL = gb: AF204171.1 gb: NM_022361.1”


FLJ10315:
“gb: NM_018056.1 /DEF = Homo sapiens
218770_s_at


hypothetical
hypothetical protein FLJ10315


protein FLJ10315
(FLJ10315), mRNA. /FEA = mRNA


(LOC55116)
/GEN = FLJ10315 /PROD = hypothetical


SEQ ID NOS: 83
protein FLJ10315


(DNA) and 282
/DB_XREF = gi: 8922347 /UG = Hs.25544


(amino acid)
hypothetical protein FLJ10315



/FL = gb: AL136695.1 gb: NM_018056.1”


PSMB9:
“gb: NM_002800.1 /DEF = Homo sapiens
204279_at
proteolysis


proteasome
proteasome (prosome, macropain)

and


(prosome,
subunit, beta type, 9 (large

peptidolysis,


macropain)
multifunctional protease 2) (PSMB9),

ubiquitin-


subunit, beta type,
mRNA. /FEA = mRNA /GEN = PSMB9

dependent


9 (large
/PROD = proteasome (prosome,

protein


multifunctional
macropain) subunit, betatype, 9 (large

catabolism


protease 2)
multifunctional protease 2)


(LOC5698)
/DB_XREF = gi: 4506204 /UG = Hs.9280


SEQ ID NOS: 84
proteasome (prosome, macropain)


(DNA) and 283
subunit, beta type, 9 (large


(amino acid)
multifunctional protease 2)



/FL = gb: U01025.1 gb: NM_002800.1”


DEPDC1: DEP
“gb: NM_017779.1 /DEF = Homo sapiens
220295_x_at


domain containing
hypothetical protein FLJ20354


1 (LOC55635)
(FLJ20354), mRNA. /FEA = mRNA


SEQ ID NOS: 85
/GEN = FLJ20354 /PROD = hypothetical


(DNA) and 284
protein FLJ20354


(amino acid)
/DB_XREF = gi: 8923327



/UG = Hs.133260 hypothetical protein



FLJ20354 /FL = gb: NM_017779.1”


EGFR: epidermal
Consensus includes gb: AW157070
201983_s_at
EGF


growth factor
/FEA = EST /DB_XREF = gi: 6228471

receptor


receptor
/DB_XREF = est: au91e07.x1

signaling


(erythroblastic
/CLONE = IMAGE: 2783652

pathway


leukemia viral (v-
/UG = Hs.77432 epidermal growth factor


erb-b) oncogene
receptor (avian erythroblastic leukemia


homolog, avian)
viral (v-erb-b) oncogene homolog)


(LOC1956)
/FL = gb: NM_005228.1


SEQ ID NOS: 86


(DNA) and 285


(amino acid)


AMPD2:
Consensus includes gb: AI916249
212360_at
purine


adenosine
/FEA = EST /DB_XREF = gi: 5636104

nucleotide


monophosphate
/DB_XREF = est: wg99c01.x1

metabolism


deaminase 2
/CLONE = IMAGE: 2379360


(isoform L)
/UG = Hs.82927 adenosine


(LOC271)
monophosphate deaminase 2 (isoform L)


SEQ ID NOS: 87
/FL = gb: NM_004037.2


(DNA) and 286


(amino acid)


GLS: glutaminase
“gb: AF158555.1 /DEF = Homo sapiens
221510_s_at
glutamine


(LOC2744)
glutaminase C mRNA, complete cds.

catabolism


SEQ ID NOS: 88
/FEA = mRNA /PROD = glutaminase C


(DNA) and 287
/DB_XREF = gi: 5690371


(amino acid)
/UG = Hs.239189 glutaminase



/FL = gb: AF158555.1 gb: AF097492.1”


EBNA1BP2:
“gb: NM_006824.1 /DEF = Homo sapiens
201323_at
ribosome


EBNA1 binding
nucleolar protein p40; homolog of yeast

biogenesis


protein 2
EBNA1-binding protein (P40), mRNA.


(LOC10969)
/FEA = mRNA /GEN = P40


SEQ ID NOS: 89
/PROD = nucleolar protein p40; homolog


(DNA) and 288
of yeastEBNA1-binding protein


(amino acid)
/DB_XREF = gi: 5803110 /UG = Hs.74407



nucleolar protein p40; homolog of yeast



EBNA1-binding protein



/FL = gb: U86602.1 gb: NM_006824.1”


VIM: vimentin
Consensus includes gb: AI922599
201426_s_at


(LOC7431)
/FEA = EST /DB_XREF = gi: 5658563


SEQ ID NOS: 90
/DB_XREF = est: wm90b11.x1


(DNA) and 289
/CLONE = IMAGE: 2443197


(amino acid)
/UG = Hs.297753 vimentin



/FL = gb: BC000163.2 gb: NM_003380.1


ZNF258: zinc
“gb: NM_007167.1 /DEF = Homo sapiens
219924_s_at
development


finger protein 258
zinc finger protein 258 (ZNF258),


(LOC9204)
mRNA. /FEA = mRNA /GEN = ZNF258


SEQ ID NOS: 91
/PROD = zinc finger protein 258


(DNA) and 290
/DB_XREF = gi: 6005977


(amino acid)
/UG = Hs.301637 zinc finger protein 258



/FL = gb: AF055470.1 gb: NM_007167.1”


SGCE:
“gb: NM_003919.1 /DEF = Homo sapiens
204688_at
muscle


sarcoglycan,
sarcoglycan, epsilon (SGCE), mRNA.

development


epsilon
/FEA = mRNA /GEN = SGCE


(LOC8910)
/PROD = sarcoglycan, epsilon


SEQ ID NOS: 92
/DB_XREF = gi: 10835046


(DNA) and 291
/UG = Hs.110708 sarcoglycan, epsilon


(amino acid)
/FL = gb: NM_003919.1 gb: AF036364.1”


CD44: CD44
“gb: M24915.1 /DEF = Human CDw44
204490_s_at
cell-cell


antigen (homing
antigen, complete cds. /FEA = mRNA

adhesion


function and
/DB_XREF = gi: 180196 /UG = Hs.169610


Indian blood group
CD44 antigen (homing function and


system) (LOC960)
Indian blood group system)


SEQ ID NOS: 93
/FL = gb: NM_000610.1 gb: U40373.1


(DNA) and 292
gb: M59040.1 gb: M24915.1”


(amino acid)


SHCBP1: likely
“gb: NM_024745.1 /DEF = Homo sapiens
219493_at


ortholog of mouse
hypothetical protein FLJ22009


Shc SH2-domain
(FLJ22009), mRNA. /FEA = mRNA


binding protein 1
/GEN = FLJ22009 /PROD = hypothetical


(LOC79801)
protein FLJ22009


SEQ ID NOS: 94
/DB_XREF = gi: 13376069


(DNA) and 293
/UG = Hs.123253 hypothetical protein


(amino acid)
FLJ22009 /FL = gb: NM_024745.1”


IMP-3: IGF-II
“gb: NM_006547.1 /DEF = Homo sapiens
203820_s_at
protein


mRNA-binding
IGF-II mRNA-binding protein 3

biosynthesis


protein 3
(KOC1), mRNA. /FEA = mRNA


(LOC10643)
/GEN = KOC1 /PROD = IGF-II mRNA-


SEQ ID NOS: 95
binding protein 3


(DNA) and 294
/DB_XREF = gi: 5729900 /UG = Hs.79440


(amino acid)
IGF-II mRNA-binding protein 3



/FL = gb: U97188.1 gb: U76705.1



gb: AF117108.1 gb: NM_006547.1”


BTG3: BTG
“gb: NM_006806.1 /DEF = Homo sapiens
205548_s_at
regulation


family, member 3
BTG family, member 3 (BTG3), mRNA.

of cell


(LOC10950)
/FEA = mRNA /GEN = BTG3

cycle


SEQ ID NOS: 96
/PROD = BTG family, member 3


(DNA) and 295
/DB_XREF = gi: 5802989 /UG = Hs.77311


(amino acid)
BTG family, member 3



/FL = gb: D64110.1 gb: NM_006806.1”


RAI14: retinoic
“gb: NM_015577.1 /DEF = Homo sapiens
202052_s_at


acid induced 14
novel retinal pigment epithelial gene


(LOC26064)
(NORPEG), mRNA. /FEA = mRNA


SEQ ID NOS: 97
/GEN = NORPEG


(DNA) and 296
/PROD = DKFZP564G013 protein


(amino acid)
/DB_XREF = gi: 13470085



/UG = Hs.15165 novel retinal pigment



epithelial gene /FL = gb: NM_015577.1



gb: AF155135.1”


QKI: quaking
Consensus includes gb: AA149639
212262_at
signal


homolog, KH
/FEA = EST /DB_XREF = gi: 1720440

transduction


domain RNA
/DB_XREF = est: zl39c06.s1


binding (mouse)
/CLONE = IMAGE: 504298


(LOC9444)
/UG = Hs.15020 homolog of mouse


SEQ ID NOS: 98
quaking QKI (KH domain RNA binding


(DNA) and 297
protein) /FL = gb: AF142419.1


(amino acid)
gb: AF142422.1


CGI-100: CGI-100
“Consensus includes gb: AL117354
202194_at
intracellular


protein
/DEF = Human DNA sequence from clone

protein


(LOC50999)
RP5-976O13 on chromosome 1p21.2-22.2

transport


SEQ ID NOS: 99
Contains part of the gene for CGI-


(DNA) and 298
100 protein, 3 isoforms of the gene for


(amino acid)
M96 protein, ESTs, STSs, GSSs and a



CpG Island /FEA = mRNA_1



/DB_XREF = gi: 6822199



/UG = Hs.296155 CGI-100 protein



/FL = gb: AF151858.1 gb: NM_016040.1”


CTSZ: cathepsin Z
“gb: AF073890.1 /DEF = Homo sapiens
210042_s_at
proteolysis


(LOC1522)
cathepsin X precursor, mRNA, complete

and


SEQ ID NOS: 100
cds. /FEA = mRNA /PROD = cathepsin X

peptidolysis


(DNA) and 299
precursor /DB_XREF = gi: 3650497


(amino acid)
/UG = Hs.252549 cathepsin Z



/FL = gb: AF032906.1 gb: AF073890.1



gb: NM_001336.1 gb: AF136273.1”









The biomarkers provided in Table 2 include the nucleotide sequences of SEQ ID NOS:101-200 and the amino acid sequences of SEQ ID NOS:300-395.









TABLE 2







BIOMARKERS (RESISTANT)












Affymetrix



Unigene title and

Probe
Gene


SEQ ID NO:
Affymetrix Description
Set
Ontology





GATA3: GATA
“gb: BC003070.1 /DEF = Homo sapiens,
209604_s_at
proteolysis


binding protein 3
GATA-binding protein 3, clone

and


(LOC2625)
MGC: 2346, mRNA, complete cds.

peptidolysis


SEQ ID NOS: 101
/FEA = mRNA /PROD = GATA-binding


(DNA) and 300
protein 3 /DB_XREF = gi: 13111765


(amino acid)
/UG = Hs.169946 GATA-binding protein



3 /FL = gb: BC003070.1 gb: M69106.1



gb: NM_002051.1”


TFF1: trefoil
“gb: NM_003225.1 /DEF = Homo sapiens
205009_at
carbohydrate


factor 1 (breast
trefoil factor 1 (breast cancer, estrogen-

metabolism,


cancer, estrogen-
inducible sequence expressed in) (TFF1),

cell


inducible sequence
mRNA. /FEA = mRNA /GEN = TFF1

growth


expressed in)
/PROD = trefoil factor 1 (breast

and/or


(LOC7031)
cancer, estrogen-inducible sequence

maintenance


SEQ ID NOS: 102
expressed in) /DB_XREF = gi: 4507450


(DNA) and 301
/UG = Hs.1406 trefoil factor 1 (breast


(amino acid)
cancer, estrogen-inducible sequence



expressed in) /FL = gb: NM_003225.1”


ZFYVE21: zinc
“gb: NM_024071.1 /DEF = Homo sapiens
219929_s_at


finger, FYVE
hypothetical protein MGC2550


domain containing
(MGC2550), mRNA. /FEA = mRNA


21 (LOC79038)
/GEN = MGC2550 /PROD = hypothetical


SEQ ID NOS: 103
protein MGC2550


(DNA) and 302
/DB_XREF = gi: 13129053


(amino acid)
/UG = Hs.318498 hypothetical protein



MGC2550 /FL = gb: BC001130.1



gb: NM_024071.1”


ATP5G2: ATP
“gb: D13119.1 /DEF = Homo sapiens P2
208764_s_at
proton


synthase, H+
mRNA for ATP synthase subunit c,

transport


transporting,
complete cds. /FEA = mRNA /GEN = P2


mitochondrial F0
/PROD = ATP synthase subunit c


complex, subunit c
precursor /DB_XREF = gi: 285909


(subunit 9),
/UG = Hs.89399 ATP synthase, H+


isoform 2
transporting, mitochondrial F0 complex,


(LOC517)
subunit c (subunit 9), isoform 2


SEQ ID NOS: 104
/FL = gb: D13119.1”


(DNA) and 303


(amino acid)


EGFL5: EGF-like-
“Consensus includes gb: W68084
212830_at
metabolism


domain, multiple 5
/FEA = EST /DB_XREF = gi: 1376954


(LOC1955)
/DB_XREF = est: zd42f12.s1


SEQ ID NOS: 105
/CLONE = IMAGE: 343343 /UG = Hs.5599


(DNA) and 304
EGF-like-domain, multiple 5”


(amino acid)


MCCC2:
“gb: AB050049.1 /DEF = Homo sapiens
209624_s_at
leucine


methylcrotonoyl-
mccb mRNA for non-biotin containing

catabolism


Coenzyme A
subunit of 3-methylcrotonyl-CoA


carboxylase 2
carboxylase, complete cds.


(beta)
/FEA = mRNA /GEN = mccb /PROD = non-


(LOC64087)
biotin containing subunit of3-


SEQ ID NOS: 106
methylcrotonyl-CoA carboxylase


(DNA) and 305
/DB_XREF = gi: 10934058


(amino acid)
/UG = Hs.167531 methylcrotonoyl-



Coenzyme A carboxylase 2 (beta)



/FL = gb: AB050049.1 gb: AF310971.1



gb: AF301000.1 gb: NM_022132.2”


ABAT: 4-
“gb: AF237813.1 /DEF = Homo sapiens
209460_at


aminobutyrate
NPD009 mRNA, complete cds.


aminotransferase
/FEA = mRNA /PROD = NPD009


(LOC18)
/DB_XREF = gi: 9963907


SEQ ID NOS: 107
/UG = Hs.283675 NPD009 protein


(DNA) and 306
/FL = gb: NM_020686.1 gb: AF237813.1”


(amino acid)


—: Clone
“Consensus includes gb: AV700224
208774_at
signal


IMAGE: 3869896,
/FEA = EST /DB_XREF = gi: 10302195

transduction


mRNA
/DB_XREF = est: AV700224


(LOC388434)
/CLONE = GKCARG01 /UG = Hs.75852


SEQ ID NOS: 108
casein kinase 1, delta


(DNA)
/FL = gb: BC003558.1”


FEM1B: fem-1
Consensus includes gb: AI799061
212367_at
induction


homolog b (C. elegans)
/FEA = EST /DB_XREF = gi: 5364533

of


(LOC10116)
/DB_XREF = est: we98a10.x1

apoptosis


SEQ ID NOS: 109
/CLONE = IMAGE: 2349114


(DNA) and 307
/UG = Hs.6048 FEM-1 (C. elegans)


(amino acid)
homolog b /FL = gb: AF178632.1



gb: NM_015322.1 gb: AF204883.1


SLC35A1: solute
“gb: NM_006416.1 /DEF = Homo sapiens
203306_s_at


carrier family 35
solute carrier family 35 (CMP-sialic acid


(CMP-sialic acid
transporter), member 1 (SLC35A1),


transporter),
mRNA. /FEA = mRNA /GEN = SLC35A1


member A1
/PROD = solute carrier family 35 (CMP-


(LOC10559)
sialic acidtransporter), member 1


SEQ ID NOS: 110
/DB_XREF = gi: 5453620 /UG = Hs.82921


(DNA) and 308
solute carrier family 35 (CMP-sialic acid


(amino acid)
transporter), member 1 /FL = gb: D87969.1



gb: NM_006416.1”


ZNF607: zinc
Consensus includes gb: AL560017
200658_s_at
DNA


finger protein 607
/FEA = EST /DB_XREF = gi: 12906073

metabolism


(LOC84775)
/DB_XREF = est: AL560017


SEQ ID NOS: 111
/CLONE = CS0DG004YD08 (5 prime)


(DNA) and 309
/UG = Hs.75323 prohibitin


(amino acid)
/FL = gb: NM_002634.2


FLJ11164:
“gb: NM_018346.1 /DEF = Homo sapiens
218307_at


hypothetical
hypothetical protein FLJ11164


protein FLJ11164
(FLJ11164), mRNA. /FEA = mRNA


(LOC55316)
/GEN = FLJ11164 /PROD = hypothetical


SEQ ID NOS: 112
protein FLJ11164


(DNA) and 310
/DB_XREF = gi: 8922910 /UG = Hs.8033


(amino acid)
hypothetical protein FLJ11164



/FL = gb: NM_018346.1”


ABAT: 4-
“gb: NM_000663.1 /DEF = Homo sapiens
206527_at
aminobutyrate


aminobutyrate
4-aminobutyrate aminotransferase

metabolism


aminotransferase
(ABAT), nuclear gene encoding


(LOC18)
mitochondrial protein, mRNA.


SEQ ID NOS: 113
/FEA = mRNA /GEN = ABAT /PROD = 4-


(DNA) and 311
aminobutyrate aminotransferase


(amino acid)
precursor /DB_XREF = gi: 4501846



/UG = Hs.1588 4-aminobutyrate



aminotransferase /FL = gb: NM_000663.1



gb: L32961.1”


SLC19A2: solute
“gb: AF153330.1 /DEF = Homo sapiens
209681_at
small


carrier family 19
thiamine carrier 1 (TC1) mRNA,

molecule


(thiamine
complete cds. /FEA = mRNA /GEN = TC1

transport


transporter),
/PROD = thiamine carrier 1


member 2
/DB_XREF = gi: 5453325 /UG = Hs.30246


(LOC10560)
solute carrier family 19 (thiamine


SEQ ID NOS: 114
transporter), member 2


(DNA) and 312
/FL = gb: AF153330.1 gb: AF135488.1


(amino acid)
gb: AF160812.1”


SLC9A3R1: solute
“gb: NM_004252.1 /DEF = Homo sapiens
201349_at
intracellular


carrier family 9
solute carrier family 9 (sodiumhydrogen

signaling


(sodium/hydrogen
exchanger), isoform 3 regulatory factor 1

cascade


exchanger),
(SLC9A3R1), mRNA. /FEA = mRNA


isoform 3 regulator
/GEN = SLC9A3R1 /PROD = solute carrier


1 (LOC9368)
family 9 (sodiumhydrogenexchanger),


SEQ ID NOS: 115
isoform 3 regulatory factor 1


(DNA) and 313
/DB_XREF = gi: 4759139


(amino acid)
/UG = Hs.184276 solute carrier family 9



(sodiumhydrogen exchanger), isoform 3



regulatory factor 1 /FL = gb: BC001443.1



gb: BC003361.1 gb: AF036241.1



gb: AF015926.1 gb: NM_004252.1”


ICA1: islet cell
“gb: L21181.1 /DEF = Human autoantigen
210547_x_at


autoantigen 1,
p69 mRNA, complete cds. /FEA = mRNA


69 kDa (LOC3382)
/PROD = autoantigen p69


SEQ ID NOS: 116
/DB_XREF = gi: 437366 /UG = Hs.167927


(DNA) and 314
islet cell autoantigen 1 (69 kD)


(amino acid)
/FL = gb: L21181.1”


CIRBP: cold
“gb: NM_001280.1 /DEF = Homo sapiens
200811_at
response


inducible RNA
cold inducible RNA-binding protein

to cold


binding protein
(CIRBP), mRNA. /FEA = mRNA


(LOC1153)
/GEN = CIRBP /PROD = cold inducible


SEQ ID NOS: 117
RNA-binding protein


(DNA) and 315
/DB_XREF = gi: 4502846


(amino acid)
/UG = Hs.119475 cold inducible RNA-



binding protein /FL = gb: D78134.1



gb: BC000403.1 gb: BC000901.1



gb: AF021336.1 gb: NM_001280.1”


C14orf114:
“gb: NM_018199.1 /DEF = Homo sapiens
218363_at


chromosome 14
hypothetical protein FLJ10738


open reading
(FLJ10738), mRNA. /FEA = mRNA


frame 114
/GEN = FLJ10738 /PROD = hypothetical


(LOC55218)
protein FLJ10738


SEQ ID NOS: 118
/DB_XREF = gi: 8922630 /UG = Hs.5457


(DNA) and 316
hypothetical protein FLJ10738


(amino acid)
/FL = gb: BC001962.1 gb: NM_018199.1”


GREB1: GREB1
“gb: NM_014668.1 /DEF = Homo sapiens
205862_at


protein
KIAA0575 gene product (KIAA0575),


(LOC9687)
mRNA. /FEA = mRNA /GEN = KIAA0575


SEQ ID NOS: 119
/PROD = KIAA0575 gene product


(DNA) and 317
/DB_XREF = gi: 7662187


(amino acid)
/UG = Hs.193914 KIAA0575 gene



product /FL = gb: AB011147.1



gb: NM_014668.1”


ESR1: estrogen
“gb: NM_000125.1 /DEF = Homo sapiens
205225_at
nuclear


receptor 1
estrogen receptor 1 (ESR1), mRNA.

hormone


(LOC2099)
/FEA = mRNA /GEN = ESR1

receptor,


SEQ ID NOS: 120
/PROD = estrogen receptor 1

cellular


(DNA) and 318
/DB_XREF = gi: 4503602 /UG = Hs.1657

proliferation


(amino acid)
estrogen receptor 1

and



/FL = gb: NM_000125.1”

differentiation


ABAT: 4-
“gb: AF237813.1 /DEF = Homo sapiens
209459_s_at


aminobutyrate
NPD009 mRNA, complete cds.


aminotransferase
/FEA = mRNA /PROD = NPD009


(LOC18)
/DB_XREF = gi: 9963907


SEQ ID NOS: 121
/UG = Hs.283675 NPD009 protein


(DNA) and 319
/FL = gb: NM_020686.1 gb: AF237813.1”


(amino acid)


ABCG1: ATP-
“gb: NM_004915.2 /DEF = Homo sapiens
204567_s_at
small


binding cassette,
ATP-binding cassette, sub-family G

molecule


sub-family G
(WHITE), member 1 (ABCG1),

transport


(WHITE), member
transcript variant 1, mRNA.


1 (LOC9619)
/FEA = mRNA /GEN = ABCG1


SEQ ID NOS: 122
/PROD = ATP-binding cassette sub-


(DNA) and 320
family G member 1isoform a


(amino acid)
/DB_XREF = gi: 8051574 /UG = Hs.10237



ATP-binding cassette, sub-family G



(WHITE), member 1



/FL = gb: NM_004915.2”


SLC35B1: solute
“gb: NM_005827.1 /DEF = Homo sapiens
202433_at
transport


carrier family 35,
UDP-galactose transporter related


member B1
(UGTREL1), mRNA. /FEA = mRNA


(LOC10237)
/GEN = UGTREL1 /PROD = UDP-


SEQ ID NOS: 123
galactose transporter related


(DNA) and 321
/DB_XREF = gi: 5032212


(amino acid)
/UG = Hs.154073 UDP-galactose



transporter related /FL = gb: D87989.1



gb: NM_005827.1”


TOB1: transducer
“Consensus includes gb: AA675892
202704_at
negative


of ERBB2, 1
/FEA = EST /DB_XREF = gi: 2775239

regulation


(LOC10140)
/DB_XREF = est: b03503s

of cell


SEQ ID NOS: 124
/CLONE = b03503 /UG = Hs.178137

proliferation


(DNA) and 322
transducer of ERBB2, 1


(amino acid)
/FL = gb: D38305.1 gb: NM_005749.1”


FOXA1: forkhead
“gb: NM_004496.1 /DEF = Homo sapiens
204667_at
regulation


box A1
hepatocyte nuclear factor 3, alpha

of


(LOC3169)
(HNF3A), mRNA. /FEA = mRNA

transcription,


SEQ ID NOS: 125
/GEN = HNF3A /PROD = hepatocyte

DNA-


(DNA) and 323
nuclear factor 3, alpha

dependent


(amino acid)
/DB_XREF = gi: 4758533



/UG = Hs.299867 hepatocyte nuclear



factor 3, alpha /FL = gb: U39840.1



gb: NM_004496.1”


LARGE: like-
“Consensus includes gb: AB011181.2
215543_s_at
muscle


glycosyltransferase
/DEF = Homo sapiens mRNA for

maintenance,


(LOC9215)
KIAA0609 protein, partial cds.

glycosphingolipid


SEQ ID NOS: 126
/FEA = mRNA /GEN = KIAA0609

biosynthesis


(DNA) and 324
/PROD = KIAA0609 protein


(amino acid)
/DB_XREF = gi: 6683718 /UG = Hs.25220



like-glycosyltransferase”


AKT1: v-akt
“gb: NM_005163.1 /DEF = Homo sapiens
207163_s_at
signal


murine thymoma
v-akt murine thymoma viral oncogene

transduction


viral oncogene
homolog 1 (AKT1), mRNA.


homolog 1
/FEA = mRNA /GEN = AKT1


(LOC207)
/PROD = serinethreonine protein kinase


SEQ ID NOS: 127
/DB_XREF = gi: 4885060 /UG = Hs.71816


(DNA) and 325
v-akt murine thymoma viral oncogene


(amino acid)
homolog 1 /FL = gb: M63167.1



gb: NM_005163.1”


CTPS2: CTP
“gb: NM_019857.1 /DEF = Homo sapiens
219080_s_at


synthase II
CTP synthase II (CTPS2), mRNA.


(LOC56474)
/FEA = mRNA /GEN = CTPS2


SEQ ID NOS: 128
/PROD = CTP synthase II


(DNA) and 326
/DB_XREF = gi: 9789918 /UG = Hs.58553


(amino acid)
CTP synthase II /FL = gb: AF226667.1



gb: NM_019857.1”


RBM8A: RNA
Consensus includes gb: AI738479
214113_s_at
nuclear


binding motif
/FEA = EST /DB_XREF = gi: 5100460

mRNA


protein 8A
/DB_XREF = est: wi32d06.x1

splicing,


(LOC9939)
/CLONE = IMAGE: 2391947

via


SEQ ID NOS: 129
/UG = Hs.65648 RNA binding motif

spliceosome


(DNA) and 327
protein 8A


(amino acid)


SIAH2: seven in
“gb: U76248.1 /DEF = Human hSIAH2
209339_at
small


absentia homolog
mRNA, complete cds. /FEA = mRNA

GTPase


2 (Drosophila)
/PROD = hSIAH2

mediated


(LOC6478)
/DB_XREF = gi: 2673967 /UG = Hs.20191

signal


SEQ ID NOS: 130
seven in absentia (Drosophila) homolog

transduction


(DNA) and 328
2 /FL = gb: U76248.1 gb: NM_005067.1”


(amino acid)


FLJ13855:
“gb: NM_023079.1 /DEF = Homo sapiens
217750_s_at
ubiquitin


hypothetical
hypothetical protein FLJ13855

cycle


protein FLJ13855
(FLJ13855), mRNA. /FEA = mRNA


(LOC65264)
/GEN = FLJ13855 /PROD = hypothetical


SEQ ID NOS: 131
protein FLJ13855


(DNA) and 329
/DB_XREF = gi: 12751494


(amino acid)
/UG = Hs.168232 hypothetical protein



FLJ13855 /FL = gb: NM_023079.1”


ITPK1: inositol
“gb: AF279372.1 /DEF = Homo sapiens
210740_s_at
signal


1,3,4-triphosphate
inositol 1,3,4-trisphosphate 56-kinase

transduction


5/6 kinase
mRNA, complete cds. /FEA = mRNA


(LOC3705)
/PROD = inositol 1,3,4-trisphosphate 56-


SEQ ID NOS: 132
kinase /DB_XREF = gi: 12006345


(DNA) and 330
/UG = Hs.6453 inositol 1,3,4-triphosphate


(amino acid)
56 kinase /FL = gb: AF279372.1”


SEPX1:
“gb: NM_016332.1 /DEF = Homo sapiens
217977_at


selenoprotein X, 1
selenoprotein X, 1 (SEPX1), mRNA.


(LOC51734)
/FEA = mRNA /GEN = SEPX1


SEQ ID NOS: 133
/PROD = selenoprotein X, 1


(DNA) and 331
/DB_XREF = gi: 7706510


(amino acid)
/UG = Hs.279623 selenoprotein X, 1



/FL = gb: AF187272.1 gb: BC003127.1



gb: AF166124.1 gb: NM_016332.1”


IRX5: iroquois
“gb: U90304.1 /DEF = Human iroquois-
210239_at
regulation


homeobox protein
class homeodomain protein IRX-2a

of


5 (LOC10265)
mRNA, complete cds. /FEA = mRNA

transcription,


SEQ ID NOS: 134
/PROD = iroquois-class homeodomain

DNA-


(DNA) and 332
protein IRX-2a /DB_XREF = gi: 1899219

dependent


(amino acid)
/UG = Hs.25351 iroquois homeobox



protein 5 /FL = gb: U90304.1



gb: NM_005853.1”


PTEN:
“gb: BC005821.1 /DEF = Homo sapiens,
211711_s_at
regulation


phosphatase and
phosphatase and tensin homolog

of CDK


tensin homolog
(mutated in multiple advanced cancers

activity


(mutated in
1), clone MGC: 11227, mRNA, complete


multiple advanced
cds. /FEA = mRNA /PROD = phosphatase


cancers 1)
and tensin homolog (mutated inmultiple


(LOC5728)
advanced cancers 1)


SEQ ID NOS: 135
/DB_XREF = gi: 13543309


(DNA) and 333
/FL = gb: BC005821.1”


(amino acid)


DP1: polyposis
“gb: BC000232.1 /DEF = Homo sapiens,
208873_s_at


locus protein 1
Similar to deleted in polyposis 1, clone


(LOC7905)
MGC: 2267, mRNA, complete cds.


SEQ ID NOS: 136
/FEA = mRNA /PROD = Similar to deleted


(DNA) and 334
in polyposis 1 /DB_XREF = gi: 12652946


(amino acid)
/UG = Hs.178112 DNA segment, single



copy probe LNS-CAILNS-CAII (deleted



in polyposis /FL = gb: BC000232.1”


KIAA1002:
“gb: NM_014925.1 /DEF = Homo sapiens
203831_at


KIAA1002 protein
KIAA1002 protein (KIAA1002), mRNA.


(LOC22864)
/FEA = mRNA /GEN = KIAA1002


SEQ ID NOS: 137
/PROD = KIAA1002 protein


(DNA) and 335
/DB_XREF = gi: 7662441


(amino acid)
/UG = Hs.102483 KIAA1002 protein



/FL = gb: AB023219.1 gb: AF113695.1



gb: NM_014925.1”


PDCD4:
“Consensus includes gb: N92498
212593_s_at
apoptosis


programmed cell
/FEA = EST /DB_XREF = gi: 1264807


death 4 (neoplastic
/DB_XREF = est: zb28a04.s1


transformation
/CLONE = IMAGE: 304878


inhibitor)
/UG = Hs.326248 Homo sapiens cDNA:


(LOC27250)
FLJ22071 fis, clone HEP11691”


SEQ ID NOS: 138


(DNA) and 336


(amino acid)


APPBP2: amyloid
Consensus includes gb: AV681579
202629_at
intracellular


beta precursor
/FEA = EST /DB_XREF = gi: 10283442

protein


protein
/DB_XREF = est: AV681579

transport


(cytoplasmic tail)
/CLONE = GKBAFE05 /UG = Hs.84084


binding protein 2
amyloid beta precursor protein


(LOC10513)
(cytoplasmic tail)-binding protein 2


SEQ ID NOS: 139
/FL = gb: AF017782.1 gb: NM_006380.1


(DNA) and 337


(amino acid)


ACVR1B: activin
Consensus includes gb: AL117643.1
213198_at
transmembrane


A receptor, type IB
/DEF = Homo sapiens mRNA; cDNA

receptor


(LOC91)
DKFZp434M245 (from clone

protein


SEQ ID NOS: 140
DKFZp434M245). /FEA = mRNA

serine/threonine


(DNA) and 338
/DB_XREF = gi: 5912233 /UG = Hs.5288

kinase


(amino acid)

Homo sapiens mRNA; cDNA


signaling



DKFZp434M245 (from clone

pathway



DKFZp434M245)


TLE3: transducin-
Consensus includes gb: AW873621
212770_at
regulation


like enhancer of
/FEA = EST /DB_XREF = gi: 8007674

of


split 3 (E(sp1)
/DB_XREF = est: ho64d03.x1

transcription,


homolog,
/CLONE = IMAGE: 3042149

DNA-



Drosophila)

/UG = Hs.31305 KIAA1547 protein

dependent


(LOC7090)


SEQ ID NOS: 141


(DNA) and 339


(amino acid)


CIRBP: cold
“gb: NM_001280.1 /DEF = Homo sapiens
200810_s_at
response


inducible RNA
cold inducible RNA-binding protein

to cold


binding protein
(CIRBP), mRNA. /FEA = mRNA


(LOC1153)
/GEN = CIRBP /PROD = cold inducible


SEQ ID NOS: 142
RNA-binding protein


(DNA) and 340
/DB_XREF = gi: 4502846


(amino acid)
/UG = Hs.119475 cold inducible RNA-



binding protein /FL = gb: D78134.1



gb: BC000403.1 gb: BC000901.1



gb: AF021336.1 gb: NM_001280.1”


ABCA3: ATP-
“gb: NM_001089.1 /DEF = Homo sapiens
204343_at
drug


binding cassette,
ATP-binding cassette, sub-family A

resistance


sub-family A
(ABC1), member 3 (ABCA3), mRNA.


(ABC1), member
/FEA = mRNA /GEN = ABCA3


3 (LOC21)
/PROD = ATP-binding cassette, sub-


SEQ ID NOS: 143
family A member 3


(DNA) and 341
/DB_XREF = gi: 4501848 /UG = Hs.26630


(amino acid)
ATP-binding cassette, sub-family A



(ABC1), member 3 /FL = gb: U78735.1



gb: NM_001089.1”


MTSS1:
“gb: NM_014751.1 /DEF = Homo sapiens
203037_s_at


metastasis
KIAA0429 gene product (KIAA0429),


suppressor 1
mRNA. /FEA = mRNA /GEN = KIAA0429


(LOC9788)
/PROD = KIAA0429 gene product


SEQ ID NOS: 144
/DB_XREF = gi: 7662113 /UG = Hs.77694


(DNA) and 342
KIAA0429 gene product


(amino acid)
/FL = gb: AB007889.1 gb: NM_014751.1”


CA12: carbonic
“gb: NM_001218.2 /DEF = Homo sapiens
203963_at
one-


anhydrase XII
carbonic anhydrase XII (CA12), mRNA.

carbon


(LOC771)
/FEA = mRNA /GEN = CA12

compound


SEQ ID NOS: 145
/PROD = carbonic anhydrase XII

metabolism


(DNA) and 343
precursor /DB_XREF = gi: 9951924


(amino acid)
/UG = Hs.5338 carbonic anhydrase XII



/FL = gb: AF037335.1 gb: AF051882.1



gb: NM_001218.2”


FRAT2: frequently
“gb: AB045118.1 /DEF = Homo sapiens
209864_at


rearranged in
FRAT2 mRNA, complete cds.


advanced T-cell
/FEA = mRNA /GEN = FRAT2


lymphomas 2
/PROD = FRAT2


(LOC23401)
/DB_XREF = gi: 13365650


SEQ ID NOS: 146
/UG = Hs.140720 GSK-3 binding protein


(DNA) and 344
FRAT2 /FL = gb: AB045118.1”


(amino acid)


SUPT4H1:
“gb: NM_003168.1 /DEF = Homo sapiens
201484_at
chromatin


suppressor of Ty 4
suppressor of Ty (S. cerevisiae) 4

modeling


homolog 1 (S. cerevisiae)
homolog 1 (SUPT4H1), mRNA.


(LOC6827)
/FEA = mRNA /GEN = SUPT4H1


SEQ ID NOS: 147
/PROD = suppressor of Ty (S. cerevisiae) 4


(DNA) and 345
homolog 1 /DB_XREF = gi: 4507310


(amino acid)
/UG = Hs.79058 suppressor of Ty



(S. cerevisiae) 4 homolog 1



/FL = gb: BC002802.1 gb: U43923.1



gb: U38818.1 gb: U38817.1



gb: NM_003168.1”


UBPH: similar to
“gb: NM_019116.1 /DEF = Homo sapiens
205687_at


ubiquitin binding
similar to ubiquitin binding protein


protein
(UBPH), mRNA. /FEA = mRNA


(LOC56061)
/GEN = UBPH /PROD = similar to


SEQ ID NOS: 148
ubiquitin binding protein


(DNA) and 346
/DB_XREF = gi: 9507222


(amino acid)
/UG = Hs.288620 similar to ubiquitin



binding protein /FL = gb: NM_019116.1”


MGC50853:
“Consensus includes gb: AL043266
212400_at


hypothetical
/FEA = EST /DB_XREF = gi: 5935844


protein
/DB_XREF = est: DKFZp434L1423_s1


MGC50853
/CLONE = DKFZp434L1423


(LOC399665)
/UG = Hs.111334 ferritin, light


SEQ ID NOS: 149
polypeptide”


(DNA) and 347


(amino acid)


TBL1X:
Consensus includes gb: AV753028
213400_s_at
signal


transducin (beta)-
/FEA = EST /DB_XREF = gi: 10910876

transduction


like 1X-linked
/DB_XREF = est: AV753028


(LOC6907)
/CLONE = NPDBCD07 /UG = Hs.76536


SEQ ID NOS: 150
transducin (beta)-like 1


(DNA) and 348


(amino acid)


FLJ11280:
Consensus includes gb: AL561943
221856_s_at


hypothetical
/FEA = EST /DB_XREF = gi: 12909874


protein FLJ11280
/DB_XREF = est: AL561943


(LOC55793)
/CLONE = CS0DB002YO04 (3 prime)


SEQ ID NOS: 151
/UG = Hs.3346 hypothetical protein


(DNA) and 349
FLJ11280


(amino acid)


RHOB: ras
“Consensus includes gb: AI263909
212099_at
Rho


homolog gene
/FEA = EST /DB_XREF = gi: 3872112

protein


family, member B
/DB_XREF = est: qi08f09.x1

signal


(LOC388)
/CLONE = IMAGE: 1855913

transduction


SEQ ID NOS: 152
/UG = Hs.204354 ras homolog gene


(DNA) and 350
family, member B


(amino acid)
/FL = gb: NM_004040.1”


LASS6: LAG1
“Consensus includes gb: BG289001
212442_s_at


longevity
/FEA = EST /DB_XREF = gi: 13044404


assurance homolog
/DB_XREF = est: 602381262F1


6 (S. cerevisiae)
/CLONE = IMAGE: 4499078


(LOC253782)
/UG = Hs.101282 Homo sapiens cDNA:


SEQ ID NOS: 153
FLJ21238 fis, clone COL01115”


(DNA) and 351


(amino acid)


KIAA0515:
“Consensus includes gb: AB011087.1
212068_s_at


KIAA0515
/DEF = Homo sapiens mRNA for


(LOC84726)
KIAA0515 protein, partial cds.


SEQ ID NOS: 154
/FEA = mRNA /GEN = KIAA0515


(DNA)
/PROD = KIAA0515 protein



/DB_XREF = gi: 3043553



/UG = Hs.108945 KIAA0515 protein”


MCCC2:
Consensus includes gb: AW439494
209623_at


methylcrotonoyl-
/FEA = EST /DB_XREF = gi: 6974800


Coenzyme A
/DB_XREF = est: xt19c01.x1


carboxylase 2
/CLONE = IMAGE: 2779584


(beta)
/UG = Hs.167531 methylcrotonoyl-


(LOC64087)
Coenzyme A carboxylase 2 (beta)


SEQ ID NOS: 155
/FL = gb: AB050049.1 gb: AF310971.1


(DNA) and 352
gb: AF301000.1 gb: NM_022132.2


(amino acid)


TFF3: trefoil
“gb: NM_003226.1 /DEF = Homo sapiens
204623_at
phosphoenolpyruvate-


factor 3 (intestinal)
trefoil factor 3 (intestinal) (TFF3),

dependent


(LOC7033)
mRNA. /FEA = mRNA /GEN = TFF3

sugar


SEQ ID NOS: 156
/PROD = trefoil factor 3 (intestinal)

phosphotransferase


(DNA) and 353
/DB_XREF = gi: 4507452 /UG = Hs.82961

system


(amino acid)
trefoil factor 3 (intestinal)



/FL = gb: L08044.1 gb: L15203.1



gb: NM_003226.1”


GATA3: GATA
Consensus includes gb: AI796169
209603_at
defense


binding protein 3
/FEA = EST /DB_XREF = gi: 5361632

response


(LOC2625)
/DB_XREF = est: wh43d10.x1


SEQ ID NOS: 157
/CLONE = IMAGE: 2383507


(DNA) and 354
/UG = Hs.169946 GATA-binding protein


(amino acid)
3 /FL = gb: BC003070.1 gb: M69106.1



gb: NM_002051.1


CEBPA:
“gb: NM_004364.1 /DEF = Homo sapiens
204039_at


CCAAT/enhancer
CCAATenhancer binding protein


binding protein
(CEBP), alpha (CEBPA), mRNA.


(C/EBP), alpha
/FEA = mRNA /GEN = CEBPA


(LOC1050)
/PROD = CCAATenhancer binding


SEQ ID NOS: 158
protein (CEBP), alpha


(DNA) and 355
/DB_XREF = gi: 4757971 /UG = Hs.76171


(amino acid)
CCAATenhancer binding protein



(CEBP), alpha /FL = gb: NM_004364.1”


LOC92482:
“Consensus includes gb: AK025724.1
213224_s_at


hypothetical
/DEF = Homo sapiens cDNA: FLJ22071


protein LOC92482
fis, clone HEP11691. /FEA = mRNA


(LOC92482)
/DB_XREF = gi: 10438333


SEQ ID NOS: 159
/UG = Hs.326248 Homo sapiens cDNA:


(DNA)
FLJ22071 fis, clone HEP11691”


FLJ13910:
Consensus includes gb: BF671894
212482_at


hypothetical
/FEA = EST /DB_XREF = gi: 11945789


protein FLJ13910
/DB_XREF = est: 602151796F1


(LOC64795)
/CLONE = IMAGE: 4292999


SEQ ID NOS: 160
/UG = Hs.75277 hypothetical protein


(DNA) and 356
FLJ13910


(amino acid)


C14orf130:
“gb: NM_018108.1 /DEF = Homo sapiens
218108_at


chromosome 14
hypothetical protein FLJ10483


open reading
(FLJ10483), mRNA. /FEA = mRNA


frame 130
/GEN = FLJ10483 /PROD = hypothetical


(LOC55148)
protein FLJ10483


SEQ ID NOS: 161
/DB_XREF = gi: 8922451 /UG = Hs.6877


(DNA) and 357
hypothetical protein FLJ10483


(amino acid)
/FL = gb: NM_018108.1”


CDKN1B: cyclin-
“gb: BC001971.1 /DEF = Homo sapiens,
209112_at
regulation


dependent kinase
Similar to cyclin-dependent kinase

of CDK


inhibitor 1B (p27,
inhibitor 1B (p27, Kip1), clone

activity


Kip1) (LOC1027)
MGC: 5304, mRNA, complete cds.


SEQ ID NOS: 162
/FEA = mRNA /PROD = Similar to cyclin-


(DNA) and 358
dependent kinase inhibitor 1B (p27, Kip1)


(amino acid)
/DB_XREF = gi: 12805034



/UG = Hs.238990 cyclin-dependent kinase



inhibitor 1B (p27, Kip1)



/FL = gb: BC001971.1 gb: NM_004064.1



gb: U10906.1 gb: AF247551.1



gb: AY004255.1”


APPBP2: amyloid
“gb: NM_006380.1 /DEF = Homo sapiens
202631_s_at
intracellular


beta precursor
amyloid beta precursor protein

protein


protein
(cytoplasmic tail)-binding protein 2

transport


(cytoplasmic tail)
(APPBP2), mRNA. /FEA = mRNA


binding protein 2
/GEN = APPBP2 /PROD = amyloid beta


(LOC10513)
precursor protein (cytoplasmictail)-


SEQ ID NOS: 163
binding protein 2


(DNA) and 359
/DB_XREF = gi: 5453552 /UG = Hs.84084


(amino acid)
amyloid beta precursor protein



(cytoplasmic tail)-binding protein 2



/FL = gb: AF017782.1 gb: NM_006380.1”


LOC81558:
“gb: NM_030802.1 /DEF = Homo sapiens
221249_s_at


C/EBP-induced
CEBP-induced protein (LOC81558),


protein
mRNA. /FEA = mRNA /GEN = LOC81558


(LOC81558)
/PROD = CEBP-induced protein


SEQ ID NOS: 164
/DB_XREF = gi: 13540589


(DNA) and 360
/FL = gb: NM_030802.1”


(amino acid)


FLJ20274:
Consensus includes gb: AL134904
213025_at


hypothetical
/FEA = EST /DB_XREF = gi: 6603091


protein FLJ20274
/DB_XREF = est: DKFZp762M0710_s1


(LOC55623)
/CLONE = DKFZp762M0710


SEQ ID NOS: 165
/UG = Hs.268371 hypothetical protein


(DNA) and 361
FLJ20274


(amino acid)


RAB11A:
“gb: NM_004663.1 /DEF = Homo sapiens
200864_s_at
intracellular


RAB11A, member
RAB11A, member RAS oncogene family

protein


RAS oncogene
(RAB11A), mRNA. /FEA = mRNA

transport


family (LOC8766)
/GEN = RAB11A /PROD = RAB11A,


SEQ ID NOS: 166
member RAS oncogene family


(DNA) and 362
/DB_XREF = gi: 4758983 /UG = Hs.75618


(amino acid)
RAB11A, member RAS oncogene family



/FL = gb: AF000231.1 gb: NM_004663.1”


—: MRNA; cDNA
Consensus includes gb: BE967207
212114_at


DKFZp313P052
/FEA = EST /DB_XREF = gi: 11773627


(from clone
/DB_XREF = est: 601661094R1


DKFZp313P052)
/CLONE = IMAGE: 3916174


(LOC387869)
/UG = Hs.165590 ribosomal protein S13


SEQ ID NOS: 167


(DNA) and 363


(amino acid)


NPEPPS:
“Consensus includes gb: AJ132583.1
201455_s_at
proteolysis


aminopeptidase
/DEF = Homo sapiens mRNA for

and


puromycin
puromycin sensitive aminopeptidase,

peptidolysis


sensitive
partial. /FEA = mRNA


(LOC9520)
/PROD = puromycin sensitive


SEQ ID NOS: 168
aminopeptidase /DB_XREF = gi: 4210725


(DNA) and 364
/UG = Hs.293007 aminopeptidase


(amino acid)
puromycin sensitive



/FL = gb: NM_006310.1”


UBL3: ubiquitin-
“gb: AF044221.1 /DEF = Homo sapiens
201534_s_at


like 3 (LOC5412)
HCG-1 protein (HCG-1) mRNA,


SEQ ID NOS: 169
complete cds. /FEA = mRNA


(DNA) and 365
/GEN = HCG-1 /PROD = HCG-1 protein


(amino acid)
/DB_XREF = gi: 4105251



/UG = Hs.173091 ubiquitin-like 3



/FL = gb: AF044221.1 gb: AL080177.1



gb: NM_007106.1”


BAMBI: BMP and
“gb: NM_012342.1 /DEF = Homo sapiens
203304_at


activin membrane-
putative transmembrane protein (NMA),


bound inhibitor
mRNA. /FEA = mRNA /GEN = NMA


homolog (Xenopus
/PROD = putative transmembrane protein



laevis)

/DB_XREF = gi: 6912533 /UG = Hs.78776


(LOC25805)
putative transmembrane protein


SEQ ID NOS: 170
/FL = gb: U23070.1 gb: NM_012342.1”


(DNA) and 366


(amino acid)


GABPB2: GA
“gb: NM_005254.2 /DEF = Homo sapiens
204618_s_at
regulation


binding protein
GA-binding protein transcription factor,

of


transcription
beta subunit 1 (53 kD) (GABPB1),

transcription,


factor, beta subunit
transcript variant beta, mRNA.

DNA-


2, 47 kDa
/FEA = mRNA /GEN = GABPB1

dependent


(LOC2553)
/PROD = GA-binding protein


SEQ ID NOS: 171
transcription factor, betasubunit 1


(DNA) and 367
(53 kD), isoform beta 1


(amino acid)
/DB_XREF = gi: 8051592 /UG = Hs.78915



GA-binding protein transcription factor,



beta subunit 1 (53 kD) /FL = gb: U13045.1



gb: NM_005254.2”


MAPT:
“gb: J03778.1 /DEF = Human microtubule-
206401_s_at
microtubule


microtubule-
associated protein tau mRNA, complete

cytoskeleton


associated protein
cds. /FEA = mRNA /GEN = MTBT1

organization


tau (LOC4137)
/DB_XREF = gi: 338684 /UG = Hs.101174

and


SEQ ID NOS: 172
microtubule-associated protein tau

biogenesis


(DNA) and 368
/FL = gb: BC000558.1 gb: J03778.1


(amino acid)
gb: NM_016841.1”


WBSCR21:
Consensus includes gb: AI923458
221927_s_at


Williams Beuren
/FEA = EST /DB_XREF = gi: 5659422


syndrome
/DB_XREF = est: wn85h04.x1


chromosome
/CLONE = IMAGE: 2452663


region 21
/UG = Hs.182476 Homo sapiens clone


(LOC83451)
PP1226 unknown mRNA


SEQ ID NOS: 173


(DNA) and 369


(amino acid)


ZNF278: zinc
“gb: AF242522.1 /DEF = Homo sapiens
211392_s_at


finger protein 278
krueppel-related zinc finger protein


(LOC23598)
SBZF5 mRNA, complete cds.


SEQ ID NOS: 174
/FEA = mRNA /PROD = krueppel-related


(DNA) and 370
zinc finger protein SBZF5


(amino acid)
/DB_XREF = gi: 9802041 /UG = Hs.27801



zinc finger protein 278



/FL = gb: AF242522.1”


SUPT4H1:
“gb: BC002802.1 /DEF = Homo sapiens,
201483_s_at
chromatin


suppressor of Ty 4
suppressor of Ty (S. cerevisiae) 4

modeling


homolog 1 (S. cerevisiae)
homolog 1, clone MGC: 3864, mRNA,


(LOC6827)
complete cds. /FEA = mRNA


SEQ ID NOS: 175
/PROD = suppressor of Ty (S. cerevisiae) 4


(DNA) and 371
homolog 1 /DB_XREF = gi: 12803910


(amino acid)
/UG = Hs.79058 suppressor of Ty



(S. cerevisiae) 4 homolog 1



/FL = gb: BC002802.1 gb: U43923.1



gb: U38818.1 gb: U38817.1



gb: NM_003168.1”


RAB4B: RAB4B,
“gb: NM_016154.1 /DEF = Homo sapiens
219807_x_at


member RAS
ras-related GTP-binding protein 4b


oncogene family
(RAB4B), mRNA. /FEA = mRNA


(LOC53916)
/GEN = RAB4B /PROD = ras-related GTP-


SEQ ID NOS: 176
binding protein 4b


(DNA) and 372
/DB_XREF = gi: 7706672


(amino acid)
/UG = Hs.279771 Homo sapiens



TR00071289_m (RAB4B), mRNA



/FL = gb: AF165522.1 gb: NM_016154.1”


PEX11B:
“gb: NM_003846.1 /DEF = Homo sapiens
202658_at
peroxisome


peroxisomal
peroxisomal biogenesis factor 11B

organization


biogenesis factor
(PEX11B), mRNA. /FEA = mRNA

and


11B (LOC8799)
/GEN = PEX11B /PROD = peroxisomal

biogenesis


SEQ ID NOS: 177
biogenesis factor 11B


(DNA) and 373
/DB_XREF = gi: 4505718 /UG = Hs.83023


(amino acid)
peroxisomal biogenesis factor 11B



/FL = gb: AF093670.1 gb: AB018080.1



gb: NM_003846.1”


LASS6: LAG1
“Consensus includes gb: AI658534
212446_s_at


longevity
/FEA = EST /DB_XREF = gi: 4762104


assurance homolog
/DB_XREF = est: tu17g01.x1


6 (S. cerevisiae)
/CLONE = IMAGE: 2251344


(LOC253782)
/UG = Hs.101282 Homo sapiens cDNA:


SEQ ID NOS: 178
FLJ21238 fis, clone COL01115”


(DNA) and 374


(amino acid)


C10orf86:
“gb: BC005212.1 /DEF = Homo sapiens,
211376_s_at


chromosome 10
Similar to hypothetical protein


open reading
FLJ20003, clone MGC: 12228, mRNA,


frame 86
complete cds. /FEA = mRNA


(LOC54780)
/PROD = Similar to hypothetical protein


SEQ ID NOS: 179
FLJ20003 /DB_XREF = gi: 13528824


(DNA) and 375
/UG = Hs.258798 hypothetical protein


(amino acid)
FLJ20003 /FL = gb: BC005212.1”


PLEKHF2:
“gb: NM_024613.1 /DEF = Homo sapiens
218640_s_at


pleckstrin
hypothetical protein FLJ13187


homology domain
(FLJ13187), mRNA. /FEA = mRNA


containing, family
/GEN = FLJ13187 /PROD = hypothetical


F (with FYVE
protein FLJ13187


domain) member 2
/DB_XREF = gi: 13375826


(LOC79666)
/UG = Hs.29724 hypothetical protein


SEQ ID NOS: 180
FLJ13187 /FL = gb: NM_024613.1”


(DNA) and 376


(amino acid)


KIAA0261:
“Consensus includes gb: D87450.1
212267_at


KIAA0261
/DEF = Human mRNA for KIAA0261


(LOC23063)
gene, partial cds. /FEA = mRNA


SEQ ID NOS: 181
/GEN = KIAA0261


(DNA) and 377
/DB_XREF = gi: 1665788


(amino acid)
/UG = Hs.154978 KIAA0261 protein”


TIP120A: TBP-
gb: AL136810.1 /DEF = Homo sapiens
208839_s_at


interacting protein
mRNA; cDNA DKFZp434G0222 (from


(LOC55832)
clone DKFZp434G0222); complete cds.


SEQ ID NOS: 182
/FEA = mRNA /GEN = DKFZp434G0222


(DNA) and 378
/PROD = hypothetical protein


(amino acid)
/DB_XREF = gi: 12053130



/UG = Hs.184786 TBP-interacting protein



/FL = gb: AL136810.1


GATA3: GATA
Consensus includes gb: AI796169
209602_s_at
defense


binding protein 3
/FEA = EST /DB_XREF = gi: 5361632

response


(LOC2625)
/DB_XREF = est: wh43d10.x1


SEQ ID NOS: 183
/CLONE = IMAGE: 2383507


(DNA) and 379
/UG = Hs.169946 GATA-binding protein


(amino acid)
3 /FL = gb: BC003070.1 gb: M69106.1



gb: NM_002051.1


CGI-85: CGI-85
“gb: NM_017635.1 /DEF = Homo sapiens
218242_s_at


protein
hypothetical protein FLJ20039


(LOC51111)
(FLJ20039), mRNA. /FEA = mRNA


SEQ ID NOS: 184
/GEN = FLJ20039 /PROD = hypothetical


(DNA) and 380
protein FLJ20039


(amino acid)
/DB_XREF = gi: 8923045



/UG = Hs.267448 hypothetical protein



FLJ20039 /FL = gb: NM_017635.1”


C20orf11:
“gb: NM_017896.1 /DEF = Homo sapiens
218448_at


chromosome 20
hypothetical protein FLJ20602


open reading
(FLJ20602), mRNA. /FEA = mRNA


frame 11
/GEN = FLJ20602 /PROD = hypothetical


(LOC54994)
protein FLJ20602


SEQ ID NOS: 185
/DB_XREF = gi: 8923556


(DNA) and 381
/UG = Hs.103808 hypothetical protein


(amino acid)
FLJ20602 /FL = gb: NM_017896.1”


IGF1R: insulin-
Consensus includes gb: H05812
203628_at
signal


like growth factor
/FEA = EST /DB_XREF = gi: 869364

transduction


1 receptor
/DB_XREF = est: yl77f04.s1


(LOC3480)
/CLONE = IMAGE: 44149


SEQ ID NOS: 186
/UG = Hs.239176 insulin-like growth


(DNA) and 382
factor 1 receptor /FL = gb: NM_000875.2


(amino acid)


LOC51315:
“gb: NM_016618.1 /DEF = Homo sapiens
218303_x_at


hypothetical
hypothetical protein (LOC51315),


protein LOC51315
mRNA. /FEA = mRNA /GEN = LOC51315


(LOC51315)
/PROD = hypothetical protein


SEQ ID NOS: 187
/DB_XREF = gi: 7706155 /UG = Hs.5721


(DNA) and 383
hypothetical protein /FL = gb: AF208845.1


(amino acid)
gb: AF217520.1 gb: NM_016618.1”


PBP: prostatic
“gb: NM_002567.1 /DEF = Homo sapiens
205353_s_at


binding protein
prostatic binding protein (PBP), mRNA.


(LOC5037)
/FEA = mRNA /GEN = PBP


SEQ ID NOS: 188
/PROD = prostatic binding protein


(DNA) and 384
/DB_XREF = gi: 4505620 /UG = Hs.80423


(amino acid)
prostatic binding protein



/FL = gb: D16111.1 gb: NM_002567.1”


KIAA0602:
“Cluster Incl. AB011174: Homo sapiens
34406_at


KIAA0602 protein
mRNA for KIAA0602 protein, partial


(LOC23241)
cds /cds = (0,2889) /gb = AB011174


SEQ ID NOS: 189
/gi = 3043727 /ug = Hs.37656 /len = 3428”


(DNA)


MYST2: MYST
“gb: NM_007067.1 /DEF = Homo sapiens
200049_at
regulation


histone
histone acetyltransferase (HBOA),

of


acetyltransferase 2
mRNA. /FEA = mRNA /GEN = HBOA

transcription,


(LOC11143)
/PROD = histone acetyltransferase

DNA-


SEQ ID NOS: 190
/DB_XREF = gi: 5901961 /UG = Hs.21907

dependent


(DNA) and 385
histone acetyltransferase


(amino acid)
/FL = gb: AF074606.1 gb: AF140360.1



gb: NM_007067.1”


C6orf211:
“gb: NM_024573.1 /DEF = Homo sapiens
218195_at


chromosome 6
hypothetical protein FLJ12910


open reading
(FLJ12910), mRNA. /FEA = mRNA


frame 211
/GEN = FLJ12910 /PROD = hypothetical


(LOC79624)
protein FLJ12910


SEQ ID NOS: 191
/DB_XREF = gi: 13375745


(DNA) and 386
/UG = Hs.15929 hypothetical protein


(amino acid)
FLJ12910 /FL = gb: NM_024573.1”


C20orf149:
“gb: NM_024299.1 /DEF = Homo sapiens
218010_x_at


chromosome 20
hypothetical protein MGC2479


open reading
(MGC2479), mRNA. /FEA = mRNA


frame 149
/GEN = MGC2479 /PROD = hypothetical


(LOC79144)
protein MGC2479


SEQ ID NOS: 192
/DB_XREF = gi: 13236523


(DNA) and 387
/UG = Hs.79625 hypothetical protein


(amino acid)
MGC2479 /FL = gb: BC002531.1



gb: NM_024299.1”


LLGL2: lethal
“gb: NM_004524.1 /DEF = Homo sapiens
203713_s_at


giant larvae
lethal giant larvae (Drosophila) homolog


homolog 2
2 (LLGL2), mRNA. /FEA = mRNA


(Drosophila)
/GEN = LLGL2 /PROD = lethal giant


(LOC3993)
larvae (Drosophila) homolog 2


SEQ ID NOS: 193
/DB_XREF = gi: 4758679 /UG = Hs.3123


(DNA) and 388
lethal giant larvae (Drosophila) homolog


(amino acid)
2 /FL = gb: NM_004524.1”


KIAA0882:
Consensus includes gb: AI348094
212956_at


KIAA0882 protein
/FEA = EST /DB_XREF = gi: 4085300


(LOC23158)
/DB_XREF = est: qp61g12.x1


SEQ ID NOS: 194
/CLONE = IMAGE: 1927558


(DNA) and 389
/UG = Hs.90419 KIAA0882 protein


(amino acid)


CA12: carbonic
“gb: BC001012.1 /DEF = Homo sapiens,
204508_s_at


anhydrase XII
hypothetical protein FLJ20151, clone


(LOC771)
MGC: 1073, mRNA, complete cds.


SEQ ID NOS: 195
/FEA = mRNA /PROD = hypothetical


(DNA) and 390
protein FLJ20151


(amino acid)
/DB_XREF = gi: 12654376



/UG = Hs.279916 hypothetical protein



FLJ20151 /FL = gb: BC001012.1



gb: NM_017689.1”


SLC2A10: solute
“gb: NM_030777.1 /DEF = Homo sapiens
221024_s_at
glucose


carrier family 2
solute carrier family 2 (facilitated

transport


(facilitated glucose
glucose transporter), member 10


transporter),
(SLC2A10), mRNA. /FEA = mRNA


member 10
/GEN = SLC2A10 /PROD = solute carrier


(LOC81031)
family 2 (facilitated glucosetransporter),


SEQ ID NOS: 196
member 10 /DB_XREF = gi: 13540546


(DNA) and 391
/FL = gb: NM_030777.1”


(amino acid)


TRIM37: tripartite
“Consensus includes gb: AK022701.1
213009_s_at


motif-containing
/DEF = Homo sapiens cDNA FLJ12639


37 (LOC4591)
fis, clone NT2RM4001938, highly


SEQ ID NOS: 197
similar to Homo sapiens mRNA for


(DNA) and 392
KIAA0898 protein. /FEA = mRNA


(amino acid)
/DB_XREF = gi: 10434250 /UG = Hs.8164



Mulibrey nanism”


AP1G1: adaptor-
“Consensus includes gb: AL050025.1
215867_x_at
endocytosis


related protein
/DEF = Homo sapiens mRNA; cDNA


complex 1, gamma
DKFZp564D066 (from clone


1 subunit
DKFZp564D066); partial cds.


(LOC164)
/FEA = mRNA /GEN = DKFZp564D066


SEQ ID NOS: 198
/PROD = hypothetical protein


(DNA) and 393
/DB_XREF = gi: 4884095 /UG = Hs.5344


(amino acid)
adaptor-related protein complex 1,



gamma 1 subunit”


UBL3: ubiquitin-
“gb: NM_007106.1 /DEF = Homo sapiens
201535_at


like 3 (LOC5412)
ubiquitin-like 3 (UBL3), mRNA.


SEQ ID NOS: 199
/FEA = mRNA /GEN = UBL3


(DNA) and 394
/PROD = ubiquitin-like 3


(amino acid)
/DB_XREF = gi: 6005927



/UG = Hs.173091 ubiquitin-like 3



/FL = gb: AF044221.1 gb: AL080177.1



gb: NM_007106.1”


CYB561:
“Consensus includes gb: U06715.1
217200_x_at
secretory


cytochrome b-561
/DEF = Human cytochrome B561,

vesicle-


(LOC1534)
HCYTO B561, mRNA, partial cds.

specific


SEQ ID NOS: 200
/FEA = mRNA /GEN = B561

electron


(DNA) and 395
/PROD = HCYTO B561

transport


(amino acid)
/DB_XREF = gi: 476590 /UG = Hs.153028

protein



cytochrome b-561”









Certain biomarkers were of particular interest. Microtubule-associated protein tau was identified as one of the resistance markers, and has been shown to bind at the close site of microtubule where Taxol® binds to. It is believed that Taxol® interferes microtubule and Tau interaction, but Tau's interaction seems more resistant than Taxol® (R. Dye et al., J. Biological Chem., 268, 6847-6850 (1993)). Therefore, this further validates the observation that Tau expressing cells are more resistant to ixabepilone treatment as ixabepilone binds at the same site of Taxol® in tubulin. Another interesting resistance biomarker is estrogen receptor. In general, estrogen-receptor status is predictive of response to hormonal treatments. (J. C. Chang et al., Lancet, 362, 362-369 (2003)). However, it was interesting to observe estrogen receptor as a strong marker for the resistance to ixabepilone. ER has not been previously suggested as a predictive marker of a patient's response to chemotherapy. More interestingly, microtubule associated protein tau is estrogen induced (M. West et al., P. N. A. S. USA, 98, 11462-11467 (2001)). ER and Tau were also found as resistance markers in an analysis of Taxol® (data not provided), and this suggests that Tau and ER both are likely to be the resistance markers for microtubule-stabilizing agents such as ixabepilone and Taxol®.


Several other genes appear promising as potential markers including transporter genes (ATP-binding cassette, sub-family G (WHITE), member 1 and ATP-binding cassette, sub-family A (ABC1), member 3), Midline 1 (C. Berti et al., BMC Cell Biol., February 29; 5(1):9 (2004)), LMP7 and etc. The differential expression patterns of these biomarkers were distinct between the two phenotypes of the cell lines (sensitive and resistant). In addition, their biological functions are involved in drug resistance mechanism or related with microtubule functions. Furthermore, their differential expression patterns observed within tumors support their potential as response markers.


Microtubule-Stabilizing Agents

Agents that affect microtubule-stabilization are well known in the art. These agents have cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease.


In one aspect, the microtubule-stabilizing agent is an epothilone, or analog or derivative thereof. The epothilones, including analogs and derivatives thereof, may be found to exert microtubule-stabilizing effects similar to paclitaxel (Taxol®) and, hence, cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease.


Suitable microtubule-stabilizing agents are disclosed, for example, in the following PCT publications hereby incorporated by reference: WO93/10121; WO98/22461; WO99/02514; WO99/58534; WO00/39276; WO02/14323; WO02/72085; WO02/98868; WO03/070170; WO03/77903; WO03/78411; WO04/80458; WO04/56832; WO04/14919; WO03/92683; WO03/74053; WO03/57217; WO03/22844; WO03/103712; WO03/07924; WO02/74042; WO02/67941; WO01/81342; WO00/66589; WO00/58254; WO99/43320; WO99/42602; WO99/39694; WO99/16416; WO 99/07692; WO99/03848; WO99/01124; and WO 98/25929.


In another aspect, the microtubule-stabilizing agent is ixabepilone. Ixabepilone is a semi-synthetic analog of the natural product epothilone B that binds to tubulin in the same binding site as paclitaxel, but interacts with tubulin differently. (P. Giannakakou et al., P. N. A. S. USA, 97, 2904-2909 (2000)).


In another aspect, the microtubule-stabilizing agent is a taxane. The taxanes are well known in the art and include, for example, paclitaxel (Taxol®) and docetaxel (Taxotere®).


Biomarkers and Biomarker Sets

The invention includes individual biomarkers and biomarker sets having both diagnostic and prognostic value in disease areas in which microtubule-stabilization and/or cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease is of importance, e.g., in cancers or tumors. The biomarker sets comprise a plurality of biomarkers such as, for example, a plurality of the biomarkers provided in Table 1 and Table 2, that highly correlate with resistance or sensitivity to one or more microtubule-stabilizing agents.


The biomarker sets of the invention enable one to predict or reasonably foretell the likely effect of one or more microtubule-stabilizing agents in different biological systems or for cellular responses. The biomarker sets can be used in in vitro assays of microtubule-stabilizing agent response by test cells to predict in vivo outcome. In accordance with the invention, the various biomarker sets described herein, or the combination of these biomarker sets with other biomarkers or markers, can be used, for example, to predict how patients with cancer might respond to therapeutic intervention with one or more microtubule-stabilizing agents.


A biomarker set of cellular gene expression patterns correlating with sensitivity or resistance of cells following exposure of the cells to one or more microtubule-stabilizing agents provides a useful tool for screening one or more tumor samples before treatment with the microtubule-stabilizing agent. The screening allows a prediction of cells of a tumor sample exposed to one or more microtubule-stabilizing agents, based on the expression results of the biomarker set, as to whether or not the tumor, and hence a patient harboring the tumor, will or will not respond to treatment with the microtubule-stabilizing agent.


The biomarker or biomarker set can also be used as described herein for monitoring the progress of disease treatment or therapy in those patients undergoing treatment for a disease involving a microtubule-stabilizing agent.


The biomarkers also serve as targets for the development of therapies for disease treatment. Such targets may be particularly applicable to treatment of breast cancers or tumors. Indeed, because these biomarkers are differentially expressed in sensitive and resistant cells, their expression patterns are correlated with relative intrinsic sensitivity of cells to treatment with microtubule-stabilizing agents. Accordingly, the biomarkers highly expressed in resistant cells may serve as targets for the development of new therapies for the tumors which are resistant to microtubule-stabilizing agents.


The level of biomarker protein and/or mRNA can be determined using methods well known to those skilled in the art. For example, quantification of protein can be carried out using methods such as ELISA, 2-dimensional SDS PAGE, Western blot, immunopreciptation, immunohistochemistry, fluorescence activated cell sorting (FACS), or flow cytometry. Quantification of mRNA can be carried out using methods such as PCR, array hybridization, Northern blot, in-situ hybridization, dot-blot, Taqman, or RNAse protection assay.


Microarrays

The invention also includes specialized microarrays, e.g., oligonucleotide microarrays or cDNA microarrays, comprising one or more biomarkers, showing expression profiles that correlate with either sensitivity or resistance to one or more microtubule-stabilizing agents. Such microarrays can be employed in in vitro assays for assessing the expression level of the biomarkers in the test cells from tumor biopsies, and determining whether these test cells are likely to be resistant or sensitive to microtubule-stabilizing agents. For example, a specialized microarray can be prepared using all the biomarkers, or subsets thereof, as described herein and shown in Table 1 and Table 2. Cells from a tissue or organ biopsy can be isolated and exposed to one or more of the microtubule-stabilizing agents. Following application of nucleic acids isolated from both untreated and treated cells to one or more of the specialized microarrays, the pattern of gene expression of the tested cells can be determined and compared with that of the biomarker pattern from the control panel of cells used to create the biomarker set on the microarray. Based upon the gene expression pattern results from the cells that underwent testing, it can be determined if the cells show a resistant or a sensitive profile of gene expression. Whether or not the tested cells from a tissue or organ biopsy will respond to one or more of the microtubule-stabilizing agents and the course of treatment or therapy can then be determined or evaluated based on the information gleaned from the results of the specialized microarray analysis.


Antibodies

The invention also includes antibodies, including polyclonal or monoclonal, directed against one or more of the polypeptide biomarkers. Such antibodies can be used in a variety of ways, for example, to purify, detect, and target the biomarkers of the invention, including both in vitro and in vivo diagnostic, detection, screening, and/or therapeutic methods.


Kits

The invention also includes kits for determining or predicting whether a patient would be susceptible or resistant to a treatment that comprises one or more microtubule-stabilizing agents. The patient may have a cancer or tumor such as, for example, a breast cancer or tumor. Such kits would be useful in a clinical setting for use in testing a patient's biopsied tumor or other cancer samples, for example, to determine or predict if the patient's tumor or cancer will be resistant or sensitive to a given treatment or therapy with a microtubule-stabilizing agent. The kit comprises a suitable container that comprises: one or more microarrays, e.g., oligonucleotide microarrays or cDNA microarrays, that comprise those biomarkers that correlate with resistance and sensitivity to microtubule-stabilizing agents; one or more microtubule-stabilizing agents for use in testing cells from patient tissue specimens or patient samples; and instructions for use. In addition, kits contemplated by the invention can further include, for example, reagents or materials for monitoring the expression of biomarkers of the invention at the level of mRNA or protein, using other techniques and systems practiced in the art such as, for example, RT-PCR assays, which employ primers designed on the basis of one or more of the biomarkers described herein, immunoassays, such as enzyme linked immunosorbent assays (ELISAs), immunoblotting, e.g., Western blots, or in situ hybridization, and the like, as further described herein.


Application of Biomarkers and Biomarker Sets

The biomarkers and biomarker sets may be used in different applications. Biomarker sets can be built from any combination of biomarkers listed in Table 1 and Table 2 to make predictions about the likely effect of any microtubule-stabilizing agent in different biological systems. The various biomarkers and biomarkers sets described herein can be used, for example, as diagnostic or prognostic indicators in disease management, to predict how patients with cancer might respond to therapeutic intervention with a microtubule-stabilizing agent, and to predict how patients might respond to therapeutic intervention that affects microtubule-stabilization and/or cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease.


The biomarkers have both diagnostic and prognostic value in diseases areas in which microtubule-stabilization and/or cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease is of importance.


In accordance with the invention, cells from a patient tissue sample, e.g., a tumor or cancer biopsy, can be assayed to determine the expression pattern of one or more biomarkers prior to treatment with one or more microtubule-stabilizing agents. In one aspect, the tumor or cancer is breast cancer. Success or failure of a treatment can be determined based on the biomarker expression pattern of the cells from the test tissue (test cells), e.g., tumor or cancer biopsy, as being relatively similar or different from the expression pattern of a control set of the one or more biomarkers. Thus, if the test cells show a biomarker expression profile which corresponds to that of the biomarkers in the control panel of cells which are sensitive to the microtubule-stabilizing agent, it is highly likely or predicted that the individual's cancer or tumor will respond favorably to treatment with the microtubule-stabilizing agent. By contrast, if the test cells show a biomarker expression pattern corresponding to that of the biomarkers of the control panel of cells which are resistant to the microtubule-stabilizing agent, it is highly likely or predicted that the individual's cancer or tumor will not respond to treatment with the microtubule-stabilizing agent.


The invention also provides a method of monitoring the treatment of a patient having a disease treatable by one or more microtubule-stabilizing agents. The isolated test cells from the patient's tissue sample, e.g., a tumor biopsy or tumor sample, can be assayed to determine the expression pattern of one or more biomarkers before and after exposure to a microtubule-stabilizing agent. The resulting biomarker expression profile of the test cells before and after treatment is compared with that of one or more biomarkers as described and shown herein to be highly expressed in the control panel of cells that are either resistant or sensitive to a microtubule-stabilizing agent. Thus, if a patient's response is sensitive to treatment by a microtubule-stabilizing agent, based on correlation of the expression profile of the one or biomarkers, the patient's treatment prognosis can be qualified as favorable and treatment can continue. Also, if, after treatment with a microtubule-stabilizing agent, the test cells don't show a change in the biomarker expression profile corresponding to the control panel of cells that are sensitive to the microtubule-stabilizing agent, it can serve as an indicator that the current treatment should be modified, changed, or even discontinued. This monitoring process can indicate success or failure of a patient's treatment with a microtubule-stabilizing agent and such monitoring processes can be repeated as necessary or desired.


The biomarkers of the invention can be used to predict an outcome prior to having any knowledge about a biological system. Essentially, a biomarker can be considered to be a statistical tool. Biomarkers are useful in predicting the phenotype that is used to classify the biological system.


Although the complete function of all of the biomarkers are not currently known, some of the biomarkers are likely to be directly or indirectly involved in microtubule-stabilization and/or cytotoxic activity against rapidly proliferating cells. In addition, some of the biomarkers may function in metabolic or other resistance pathways specific to the microtubule-stabilizing agents tested. Notwithstanding, knowledge about the function of the biomarkers is not a requisite for determining the accuracy of a biomarker according to the practice of the invention.


EXAMPLES
Example 1
Identification of Biomarkers
Methods

Cell Lines and Cytotoxicity Assay


23 breast cancer cell lines were assayed for their sensitivity to ixabepilone. Each cell line was exposed to ixabepilone for 72 hours, and growth inhibition was assessed by the CellTiter 96® Aqueous Non-Radioactive Cell proliferation Assay (Promega) for IC50 measurements. Then, the concentration of the ixabepilone required for 50% growth inhibition was calculated as the IC50. For each experimental condition, at least triplicate measurements were carried out for each cell line. The 23 cell lines were assayed for their IC50 measurements twice, and these two separate IC50 data sets were used for the following analysis.


Training Set Selection


For analysis, training cell lines were chosen in the following manner. The 23 cell lines were assigned into the classes “sensitive” or “resistant” using IC50 values; log(IC50) values were normalized based on the mean and the standard deviation (SD) across the 23 cell lines for each IC50 data set. (J. E. Staunton et al., P. N. A. S. USA. 98, 10787-10792 (2001)) The cell lines with the normalized log(IC50) below the mean of log(IC50)s were classified as sensitive and above as resistant. Subsequently, classification of the cell lines were compared in two separate experiments and 18 cell lines that exhibited consistent IC50 and classification were chosen as a training set for subsequent marker analysis. Five cell lines with inconsistent IC50 and classification were considered to be intermediate and were eliminated from the analysis.


RNA Extraction and Gene Expression Data


The 23 breast cancer cell lines were grown to 50-70% confluent in RPMI media with FBS 10% at 37° C. and 5% CO2. RNA was isolated using the RNeasy Mini kit (Qiagen) according to the manufacturer's instructions. 10 ug of total RNA was used to prepare biotinylated cRNA targets as described in Affymetrix protocol. Targets were hybridized to Affymetrix high-density HU133 A and B set that consist of 44,000 probe sets containing ˜32,000 genes. The chips were washed and stained using recommended procedures for GeneChip®. Expression values were calculated and scaled to 1500 by using Affymetrix GeneChip® software.


k-Nearest Neighbors (KNN) Analysis


GeneCluster software was used to find a set of marker genes. First, genes with greater than 100 average difference were filtered. Then, genes were excluded if they varied by less than 2-fold and 1000 average difference change across 18 training cell lines. Subsequently, intensity units across the cell lines for each gene were normalized to the mean and variance. The genes were ranked according to the correlation between their expression level, and the sensitivity and resistance profile of the training cell lines. A marker gene selection process was carried out by KNN algorithm which fed only the genes with higher correlation with the target class. The KNN algorithm sets the class of the data point to the majority class appearing in the k closest training set samples. This marker selection is done by sorting the genes according to the signal-to-noise statistics, [μ1(g)−μ2(g)]/[σ1(g)+σ2(g)], described as the correlation function where [μ1(g), μ2(g)] and [σ1(g), σ2(g)] denote the means and SDs of the expression levels of gene g for the samples in class 1 and class 2, respectively. The magnitude of correlation values indicates the strength of the correlation between gene expression and class distinction.


Leave-One-Out Cross-Validation Analysis and Random Classification


Predictors with 1-250 genes were used for cross-validation of the training set. For each predictor, cross-validation was performed with the entire training set; one cell line was removed, the classifier was trained on the remaining cell lines and then tested for its ability to classify the withheld cell line. This procedure was repeated for each cell line in the training set. For random classification analysis, GeneCluster was used to generate random class vectors and calculate error rates.


Clustering and Tree View


Gene expression data were analyzed by the software Cluster and TreeView.


Breast Tumors and Gene Expression Data


RNAs extracted from 175 breast tumors resected at the surgery were obtained from the Karolinska Institute (Stockholm, Sweden). These RNA samples were profiled using Affymetrix Human U133 sets and their gene expression data were used for the analysis.


Results

Drug sensitivity data (IC50) was used as a template for determining the phenotype of the cell lines as resistant or sensitive. Initially, two separate IC50 data sets were generated for 23 breast cancer cell lines. As a first step for the analysis, the log(IC50) value for each cell line was calculated and normalized using the mean of log(IC50)s and SD across the cell lines (J. E. Staunton et al., P. N. A. S. USA. 98, 10787-10792 (2001)) in each IC50 data panel. Then the cell lines were divided into two classes using the following method; the normalized log(IC50)s above the mean are defined as resistant and below as sensitive (FIG. 1). After comparing the classification of the cell lines in the two data sets, 18 cell lines that displayed the consistent classification and IC50 values in two separate experiments were selected and utilized for marker selection.


Subsequently, the gene expression data of the 18 cell lines were analyzed to identify genes that were highly correlated with observed phenotype defined as sensitive or resistant. From the GeneCluster analysis, classifiers that consisted of up to 250 correlated genes were selected and tested through leave-one out cross validation; by holding back one cell line, training on the remaining cell lines, predicting the class of the withheld cell line, and repeating this cycle for each cell line in the training set. Each gene was ranked according to the correlation in the training set between its expression level and the sensitivity-resistance class distinction. Each classifier identified from the analysis was evaluated with the error rate as shown in the FIG. 2. In order to assess whether or not the classifiers can be observed by chance, the error rates calculated from random classification were examined. Shown as an example in FIG. 3, error rates generated from random classifications were significantly higher than that from IC50-based classification.


From the GeneCluster analysis, 200 genes (Tables 1 and 2) were identified whose expression levels were highly correlated with the sensitivity-resistance class distinction based on the KNN analysis and the T-test. Among these genes, the 50 marker candidates most closely correlated with sensitivity-resistance class distinction (first 25 sensitive markers of Table 1 and first 25 resistant markers of Table 2) were selected for further analysis.


As shown in FIG. 4, these 50 genes showed distinct expression patterns between sensitive and resistant cell lines. For example, the top 25 markers correlated with sensitivity (one of which was Proteasome subunit, beta type 8 (LMP7)) as shown in FIG. 4 were highly expressed (shown in red) in sensitive cell lines, but at a lower level (shown in blue) in the resistant cell lines. In contrast, the top 25 markers correlated with resistance showed the opposite expression pattern as these genes were highly expressed in the resistant cell lines, but at a lower level in the sensitive cell lines.


Among 200 genes identified, it is interesting to find estrogen receptor (ER) as one of the resistance markers. As shown in FIG. 4, ER expression levels were highly correlated with the resistance to ixabepilone. ER was highly expressed in the resistant cell lines, but its expression was very low in the sensitive cell lines. Although the resistance mechanism of ER is not obvious, the data suggests that ER might be involved in drug resistance associated with microtubule stabilizing agents. In fact, ER was also found as a resistance marker in our analysis of paclitaxel (data not shown). In addition to ER, a microtubule-associated protein, tau (Tau), was also identified as one of the resistance markers. This protein has been proposed to bind close to the Taxol® binding site on β-tubulin and stabilize microtubules in a similar way to Taxol® (S. Kar et al., EMBO J., 22, 70-77. (2003)). Therefore, Tau is likely to affect the Taxol® bound to microtubules and, presumably, ixabepilone in a similar way since ixabepilone binds at the same site as paclitaxel on β-tubulin. Interestingly, Tau is estrogen induced (M. West et al., P. N. A. S. USA, 98, 11462-11467 (2001)). Evidently, they seem to be co-regulated as shown in a plot of Tau expression level against ER (FIG. 5). Their correlation coefficient value is 0.7.


Among the sensitivity markers identified, LMP7 is particularly interesting because it appears to be connected to Tau's function. In general, the proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and programmed cell death, or apoptosis (P. Voorhees et al., Clin. Cancer Res., 9, 6316-6325 (2003)). Among many proteins processed by the proteasome, Tau is degraded by the 20S proteasome in vitro in an ubiquitin-independent manner (D. David et al., J. of Neurochemistry, 83, 176-185 (2002)). This supports LMP7 as one of the sensitivity markers because LMP7 presumably facilitates interaction between ixabepilone and microtubules by degrading Tau and making ixabepilone more accessible to the microtubules.


One type of drug resistance mechanism is based on the function of a group of transporter proteins, able to prevent the intracellular accumulation of anticancer drugs by an efflux mechanisms (F. Leonessa et al., Endocr. Relat. Cancer., 10, 43-73 (2003)). Several transporter genes were identified as potential resistance markers as they were highly expressed in the resistant cell lines. These genes include ATP-binding cassette, sub-family G (WHITE), member 1 and ATP-binding cassette, sub-family A (ABC1), member 3. They are ATP dependent transporters which may be involved in lipid transport, and act as an efflux pump for chemotherapeutics drugs respectively (M. Gottesman et al., Nat. Rev. Cancer., January; 2(1):48-58 (2002)).


In addition, genes implied in microtubule functions are particularly interesting since ixabepilone is a microtubule-stabilizing agents. Microtubules are essential components of the cytoskeleton and involved in cell motility and transport, and maintenance of cell shape. The dynamic nature of a microtubule whose ability to polymerize and depolymerize, is essential for the segregation of chromosomes during mitosis (C. Bode et al., Biochemistry, 41, 3870-3874 (2002)). Therefore, marker genes such as midline 1 (C. Berti et al., BMC Cell Biol., February 29; 5(1):9 (2004)) and annexin A1 (L. C. Alldridge et al., Exp. Cell Res., October 15; 290(1):93-107 (2003)) that are implied in those functions can be involved in the mechanism of drug resistance. The biomarkers are categorized by their biological functions in Tables 1 and 2.


To study the use of these genes as response prediction markers in vivo, the expression pattern of these 50 genes in 175 breast cancer biopsies obtained from the Karolinska Institute was examined. The 50 genes were used to cluster the expression patterns of tumors. As shown in FIG. 6, these tumors were found to show patterns of expression that allowed sub-classification of these tumors into distinct groups as seen in the cell line study. Among many genes, Tau and ER were examined in tumors which were identified as resistance markers from cell lines. As shown in the FIG. 7, there is a trend in which Tau and ER seem to correlate as seen in the cell line study. In fact, both genes are highly expressed in a subset of tumors. These tumors are presumed to be non-responders for ixabepilone treatment.


Example 2
Further Evaluation of ER and Tau Biomarkers

Estrogen receptor (ER) and tau (Tau) were identified as biomarkers since their expression patterns were highly correlated with resistance to ixabepilone. In addition, it was found that the ER pathway was the most implicated biological network for resistance to ixabepilone based on the pathway analysis using preclinical candidate markers (FIGS. 9 and 10). Interestingly, Tau was recently identified as the gene most correlated with pathological complete response for T/FAC neoadjuvant treatment in breast cancer patients (M. Ayers et al, J. Clin. Oncol., 22(12):2284-93 (2004); R. Rouzier et al., P.N.A.S., June 7; 102(23):8315-20 (2005)). Following this report, our preclinical study on paclitaxel supported the clinical findings of Tau as a novel mediator of paclitaxel sensitivity (P. Wagner et al., Cell Cycle, September; 4(9):1149-52 (2005)). ER and Tau were evaluated for their predictability of response to ixabepilone in CA163-080 trial.


Methods
CA163-080 Study

CA163-080 is an exploratory genomic phase II study that was conducted in breast cancer patients who received ixabepilone as a neoadjuvant treatment. The primary objective of this study was to identify predictive markers of response to ixabepilone through gene expression profiling of pre-treatment breast cancer biopsies. Patients with invasive stage IIA-IIIB breast adenocarcinoma (tumor size≧3 cm diameter) received 40 mg/m2 ixabepilone as a 3-hour infusion on Day 1 for up to four 21-day cycles, followed by surgery within 3-4 weeks of completion of chemotherapy. A total of 164 patients were enrolled in this study. Biopsies for gene expression analysis were obtained both pre- and post-treatment. Upon isolation of biopsies from the patients, samples were either snap frozen in liquid nitrogen or placed into RNAlater solution overnight, followed by removal from the RNAlater solution. All samples were kept at −70° C. until use.


Evaluation of Pathological Response

Pathological response was assessed using the Sataloff classification system (D. Sataloff et al., J. Am. Coll. Surg., 180(3):297-306 (1995)) and used as an end point for the pharmacogenomic analysis. The pathologic response was evaluated in the primary tumor site at the end of treatment and prior to surgery by assessing histologic changes compared with baseline as following: At the primary tumor site, cellular modifications were evaluated in both the infiltrating tumoral component and in the possible ductal component, to determine viable residual infiltrating component (% of total tumoral mass); residual ductal component (% of total tumoral mass); the mitotic index. Pathologic Complete Response (pCR) in the breast only was defined as T-A, Total or near total therapeutic effect in primary site. Based on this criteria, responders included patients with pCR while non-responders included patients who failed to demonstrate pCR. The response rate was defined as the number of responders divided by the number of treated patients.


Gene Expression Profiling

Total RNA was isolated using the RNeasy Mini kit (Qiagen) according to the manufacturer's instructions by Karolinska Institute (Stockholm, Sweden). A total of 134 patients with more than 1 μg of total RNA with good quality were included in the data set for the final genomic analysis. Samples were profiled in a randomized order by batches to minimize the experimental bias. Each batch consisted of about 15 subject samples and 2 experimental controls using RNA extracted from HeLa cells. The expression profiling was done following a complete randomization with an effort to balance the number of samples from two tissue collection procedures (RNAlater and liquid nitrogen), two mRNA preparation methods (standard and DNA supernatants), tissue collection sites, and time of RNA sample preparation within in each batch. The mRNA samples from each subject was processed with HG-U133A 2.0 GeneChip® arrays on the Affymetrix platform and quantitated with GeneChip® Operating Software (GCOS) V1.0 (Affymetrix). The HG-U133A 2.0 GeneChip® array consists of about 22,276 probe sets, each containing about 15 perfect match and corresponding mismatch 25mer oligonucleotide probes from specific gene sequences.


Gene Expression Data Processing

The gene expression data were transformed using base two logarithm. The Robust Multichip Average (RMA) method (C. Clopper et al., Biometrika, 26:404-13 (1934)) was used to normalize the raw expression data. The gene expression measures of each gene were centered at zero and rescaled to have a 1-unit standard deviation.


Stromal Effects in Tumor Biopsies

A hierarchical clustering analysis was performed in order to examine molecular profiles of tumor biopsies (FIG. 10). Among the two highest level clusters, the tumor samples from three Russian sites (site numbers 16, 24 and 25) were mostly clustered in the first cluster (Fisher's exact test, p-value <0.01). It appeared that genes implied in lymphocyte functions such as MHC, CD antigen, and IgG were enriched in this cluster. Therefore, this led to the concern that the tumors from the three Russian sites contained more stroma in the biopsies than other sites, thus contaminating the RNA samples with respect to gene expression for tumor tissue alone. In addition, the mean tumor size from the three Russian sites (16, 24 and 25) was larger than that for the other sites (mean 5.43 vs. mean 4.55, t-test p-value=0.022). Moreover, the pCR response rate was lower than that of the other sites (pCR 19.8% v.s. 17.2%, chi-squared p-value=0.73). This suggested that tumors from the three Russian sites were distinct from the others. Thus, a subgroup analysis excluding the three Russian sites was also performed.


Statistical Analysis

Logistic regression (F. Hsieh et al., Stat. Med., 17(14):1623-34 (1998)) was used to explore the relationships between the expression of genes and response to ixabepilone. The following model was fitted for each gene separately:







log


(


Pr


(

Y
=

1
|
X


)



1
-

Pr


(

Y
=

1
|
X


)




)


=


b
0

+


b
1


X






where Y=1 represents a responder and X is the gene expression measure. For each gene, the probability from a two-tailed Score test of whether the estimate of b1=0 was used to rank the most interesting genes for further investigation. eb1 is the odds ratio of being a non-responder for a one unit increase in gene expression relative to the average expression for the sample of subjects. Odds ratios and 95% confidence limits were reported.


Subjects were randomly assigned to the equal sized training set (n=67) or the test set (n=67), for responders and non-responders groups separately. The gene expression of ER and Tau were considered as potential predictors for response. Single logistic regression (SLR) was used to build the predictive model based on the training set, and the model performance was assessed on the test set. The prediction error, sensitivity, specificity, PPV (positive predictive value), and NPV (negative predictive value) as well as their 95% confidence intervals of the SLR model were estimated.


Results
Estrogen Receptor (ER) and Tau

For ER, patients whose predicted probability of being responders was greater than 0.3 were classified as responders. The ER prognostic sensitivity, specificity, PPV, NPV, and their 95% confidence intervals of the SLR model are 0.64 (0.35, 0.85), 0.79 (0.66, 0.87), 0.37 (0.19, 0.59), and 0.92 (0.80, 0.97), respectively. For Tau, patients whose predicted probability of being responders was greater than 0.25 were classified as responders. The Tau prognostic sensitivity, specificity, PPV, NPV, and their 95% confidence intervals of the SLR model are 0.55 (0.28, 0.79), 0.73 (0.60, 0.83), 0.29 (0.14, 0.50), and 0.89 (0.77, 0.95), respectively.


Estrogen Receptor (ER) and Tau without Russian Sites 16, 24 and 25


For ER and Tau separately as SLR predictors, patients whose predicted probability of being responders was greater than 0.5 were classified as responders. The estrogen receptor 1 prognostic sensitivity, specificity, PPV, NPV and their 95% confidence intervals of the SLR model are 0.67 (0.35, 0.88), 0.83 (0.69, 0.92), 0.46 (0.23, 0.71), and 0.92 (0.79, 0.97), respectively. The Tau prognostic sensitivity, specificity, PPV, NPV, and their 95% confidence intervals of the SLR model are 0.44 (0.19, 0.73), 0.88 (0.75, 0.95), 0.44 (0.19, 0.73), and 0.88 (0.75, 0.95), respectively.


CONCLUSION/DISCUSSION

A total of 164 patients were enrolled in CA163-080 study. The quality and quantity of RNA samples obtained from pre-treatment biopsies was fairly good as 134 patients (85%) had RNA samples with >1 μg good quality which did not require additional amplification for gene expression profiling. Stromal contamination in the tumor biopsies was raised as a potential problem for the analysis. It appeared that the three Russian sites 16, 24 and 25 might have more stromal tissues in the samples compared to others based on the hierarchical clustering analysis. In addition, the tumors from these three Russian sites were larger than others at baseline. Although further analysis is needed to confirm this hypothesis, it raised an important issue for analyzing clinical samples that are inherently heterogeneous.


Among preclinical candidate markers, ER and Tau were examined in CA163-080 for their predictability. In our preclinical work, ER and Tau had been identified as biomarkers since their expression patterns were highly correlated with resistance to ixabepilone. In CA163-080, ER predicted well for pCR whether or not the three Russian sites were included in the analysis. However, the highest PPV was obtained when these sites were excluded. In another study finding predictive markers of response to combination chemotherapy with paclitaxel, 5-Fluorouracil, adriamycin and cyclophosphamide, the ER regulated gene Tau was identified as the best predictor of response (M. Ayers et al., J. Clin. Oncol., 22(12):2284-93 (2004)). Work done by this group has also demonstrated in vitro that knocking down Tau levels using small interfering RNA (siRNA) increases the sensitivity of breast cancer cell lines to paclitaxel treatment (R. Rouzier et al., P.N.A.S., June 7; 102(23):8315-20 (2005)). The proposed mechanism is that high levels of Tau inhibit binding of paclitaxel to the taxane binding site on β-tubulin. Tau gene expression was therefore also examined for ability to predict response to ixabepilone. The PPV (0.44) with this gene was similar to that for ER (0.46) in the subset excluding the 3 Russian sites.


Thus, ER and Tau demonstrated their utility as a predictors for response to ixabepilone and can be used as biomarkers for identifying the pCR responders to ixabepilone.


Example 3
Production of Antibodies Against the Biomarkers

Antibodies against the biomarkers can be prepared by a variety of methods. For example, cells expressing a biomarker polypeptide can be administered to an animal to induce the production of sera containing polyclonal antibodies directed to the expressed polypeptides. In one aspect, the biomarker protein is prepared and isolated or otherwise purified to render it substantially free of natural contaminants, using techniques commonly practiced in the art. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity for the expressed and isolated polypeptide.


In one aspect, the antibodies of the invention are monoclonal antibodies (or protein binding fragments thereof). Cells expressing the biomarker polypeptide can be cultured in any suitable tissue culture medium, however, it is preferable to culture cells in Earle's modified Eagle's medium supplemented to contain 10% fetal bovine serum (inactivated at about 56° C.), and supplemented to contain about 10 g/l nonessential amino acids, about 1,00 U/ml penicillin, and about 100 μg/ml streptomycin.


The splenocytes of immunized (and boosted) mice can be extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line can be employed in accordance with the invention, however, it is preferable to employ the parent myeloma cell line (SP2/0), available from the ATCC (Manassas, Va.). After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (1981, Gastroenterology, 80:225-232). The hybridoma cells obtained through such a selection are then assayed to identify those cell clones that secrete antibodies capable of binding to the polypeptide immunogen, or a portion thereof.


Alternatively, additional antibodies capable of binding to the biomarker polypeptide can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens and, therefore, it is possible to obtain an antibody that binds to a second antibody. In accordance with this method, protein specific antibodies can be used to immunize an animal, preferably a mouse. The splenocytes of such an immunized animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones that produce an antibody whose ability to bind to the protein-specific antibody can be blocked by the polypeptide. Such antibodies comprise anti-idiotypic antibodies to the protein-specific antibody and can be used to immunize an animal to induce the formation of further protein-specific antibodies.


Example 4
Immunofluorescence Assays

The following immunofluorescence protocol may be used, for example, to verify biomarker protein expression on cells or, for example, to check for the presence of one or more antibodies that bind biomarkers expressed on the surface of cells. Briefly, Lab-Tek II chamber slides are coated overnight at 4° C. with 10 micrograms/milliliter (μg/ml) of bovine collagen Type II in DPBS containing calcium and magnesium (DPBS++). The slides are then washed twice with cold DPBS++ and seeded with 8000 CHO—CCR5 or CHO pC4 transfected cells in a total volume of 125 g and incubated at 37° C. in the presence of 95% oxygen/5% carbon dioxide.


The culture medium is gently removed by aspiration and the adherent cells are washed twice with DPBS++ at ambient temperature. The slides are blocked with DPBS++ containing 0.2% BSA (blocker) at 0-4° C. for one hour. The blocking solution is gently removed by aspiration, and 125 μl of antibody containing solution (an antibody containing solution may be, for example, a hybridoma culture supernatant which is usually used undiluted, or serum/plasma which is usually diluted, e.g., a dilution of about 1/100 dilution). The slides are incubated for 1 hour at 0-4° C. Antibody solutions are then gently removed by aspiration and the cells are washed five times with 400 μl of ice cold blocking solution. Next, 125 μl of 1 μg/ml rhodamine labeled secondary antibody (e.g., anti-human IgG) in blocker solution is added to the cells. Again, cells are incubated for 1 hour at 0-4° C.


The secondary antibody solution is then gently removed by aspiration and the cells are washed three times with 400 μl of ice cold blocking solution, and five times with cold DPBS++. The cells are then fixed with 125 μl of 3.7% formaldehyde in DPBS++ for 15 minutes at ambient temperature. Thereafter, the cells are washed five times with 400 μl of DPBS++ at ambient temperature. Finally, the cells are mounted in 50% aqueous glycerol and viewed in a fluorescence microscope using rhodamine filters.


Although the invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

Claims
  • 1. A method for predicting a resistance to a method of treating cancer of a mammal in need thereof comprising administering a microtubule-stabilizing agent comprising ixabepilone, wherein the method comprises: (a) exposing said mammal to said agent;(b) following the exposing of step (a), measuring in a breast cancer tissue biological sample from the mammal the level of a biomarker comprising estrogen receptor 1,wherein an increase in the level of the biomarker predicts a resistance to said method of treating cancer.
  • 2. The method of claim 1 wherein said estrogen receptor 1 comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO:318.
  • 3. The method of claim 1 wherein said estrogen receptor 1 comprises the nucleotide sequence of SEQ ID NO:120.
  • 4. The method of claim 1 wherein said estrogen receptor 1 comprises the amino acid sequence of SEQ ID NO:318.
  • 5. The method of claim 1 where said measuring comprises using the Robust Multichip Average (RMA) method to normalize expression data.
Parent Case Info

This application claims the benefit of U.S. Provisional Application No. 60/631,993 filed Nov. 30, 2004, and is a continuation of U.S. Non-Provisional application Ser. No. 11/289,102 filed Nov. 29, 2005, whose contents are hereby incorporated by reference in its entirety.

Continuations (1)
Number Date Country
Parent 11289102 Nov 2005 US
Child 11906248 US