WO2010102157A1

WO2010102157A1 - Molecular predictors of biological response to a cenpe inhibitor in cancer

Info

Publication number: WO2010102157A1
Application number: PCT/US2010/026282
Authority: WO
Inventors: Joe W. Gray; Debopriya Das; Nicholas J. Wang; Wen-Lin Kuo; Paul T. Spellman; Zhi Hu
Original assignee: The Regents Of The University Of California
Priority date: 2009-03-04
Filing date: 2010-03-04
Publication date: 2010-09-10

Abstract

Disclosed is a method for identifying a cancer patient, such as a breast cancer patient, suitable for treatment with a CENPE inhibitor, such as GSK923295A. The method involved detecting the modulated expression of CENPE and one or more of a set of predictive biomarkers, or protein encoded thereof.

Description

Molecular predictors of biological response to a CENPE inhibitor in cancer

Inventors: Joe W. Gray, Debopriya Das, Nicholas J. Wang, Wen-Lin Kuo, Paul T. Spellman, and Zhi Hu

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 61/157,507, filed on March 4, 2009, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENTAL SUPPORT

[0002] The invention described and claimed herein was made in part under Work for Others Agreement LB06-002417., under Grant No. U54 CAl 12970 awarded by the National Institutes of Health/National Cancer Institute and under Contract No. DE-AC02-05CH11231 awarded by the U.S. Department of Energy. The Government has certain rights in this invention.

REFERENCE TO SEQUENCE LISTING

[0003] This application hereby incorporates by reference the attached sequence listing in paper and computer readable form, in the .txt file titled, "2675PCT_sequences_ST25.txt", created on March 4, 2010.

FIELD OF THE INVENTION

[0004] This invention relates generally to genetic markers involved in the diagnosis and prognosis of cancer, especially breast cancer. This invention also relates to markers predictive for patient response to specific cancer therapeutics.

BACKGROUND OF THE INVENTION

[0005] Breast cancer is one of the most common malignancies among women and shares, together with lung carcinoma, the highest fatality rate of all cancers affecting females. The current treatment of the breast cancer is limited to a very invasive, total or partial mastectomy, radiation therapy, or chemotherapy, the latter two resulting in serious undesirable side effects.

[0006] It is now well established that breast cancers progress through accumulation of genomic and epigenomic aberrations that enable development of aspects of cancer pathophysiology such as reduced apoptosis, unchecked proliferation, increased motility, and increased angiogenesis. Discovery of the genes that contribute to these pathophysiologies when deregulated by recurrent aberrations is important to understanding mechanisms of cancer formation and progression and to guide improvements in cancer diagnosis and treatment.

[0007] Analyses of expression profiles have been particularly powerful in identifying distinctive breast cancer subsets that differ in biological characteristics and clinical outcome. For example, unsupervised hierarchical clustering of microarray derived expression data have identified intrinsically variable gene sets that distinguish five breast cancer subtypes - basal- like, luminal A, luminal B, ERBB2 and normal breast-like. The basal-like and ERBB2 subtypes have been associated with strongly reduced survival durations in patients treated with surgery plus radiation and some studies have suggested that reduced survival duration in poorly performing subtypes is caused by an inherently high propensity to metastasize. These analyses already have led to the development of multi-gene assays that stratify patients into groups that can be offered treatment strategies based on risk of progression. However, the predictive power of these assays is still not as high as desired and the assays have not been fully tested in patient populations treated with aggressive adjuvant chemotherapies.

[0008] Analyses of breast tumors using fluorescence in situ hybridization and comparative genomic hybridization show that breast tumors also display a number of recurrent genome copy number aberrations including regions of high level amplification that have been associated with adverse outcome. This raises the possibility of improved patient stratification through combined analysis of gene expression and genome copy number.

SUMMARY OF THE INVENTION

[0009] The invention provides for a method for identifying a cancer patient suitable for treatment with a Centromere-associated protein E (CENPE) inhibitor comprising detecting modulated expression of genes selected from the group consisting of: CACNAlD, ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2. In one embodiment, the CENPE inhibitor is GSK923295A.

[0010] The invention provides for a method for identifying a cancer patient suitable for treatment with a CENPE inhibitor, wherein the patient (a) is CENPE-positive and (b) has an increased or high expression level of 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, or ZFP36L2. Patients identified as having an increased expression of these genes are predicted to be sensitive to treatment of cancer with a CENPE inhibitor, such as GSK923295A.

[0011] In other embodiments, The invention provides for a method for identifying a cancer patient suitable for treatment with a CENPE inhibitor, wherein the patient (a) is CENPE-positive and (b) has an increased or high expression level of CACNAlD, ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, or ZNF652. If the patient is determined to have an increased of high expression level of one or more of these genes, the patient is predicted to be resistant to treatment of cancer with a CENPE inhibitor.

[0012] In some embodiments of the invention, an increased or decreased expression level is an expression level of a gene that is more than or less than, respectively, than the expression level of the same gene in a normal tissue or cell sample, such as the cell or tissue sample of non-cancerous cells of the patient or another person that does not have cancer.

[0013] In some embodiments of the invention, an increased or decreased expression level is an expression level of a gene that is more than or less than, respectively, than the average expression level of the same gene in a panel of normal cell lines or cancer cell lines

[0014] In some embodiments of the invention, an increased or decreased expression level is an expression level that is relatively more than or less than, respectively. In some embodiments, a high or low expression level of a gene is a value (a) equal to or (b) higher or lower, respectively, than the average value (Iog₂(expression)) described for the corresponding gene in Table 3.

[0015] The invention provides for a method of treating a cancer patient comprising (a) identifying a cancer patient who is suitable for treatment with a CENPE inhibitor using a method of the present invention, and (b) administering a therapeutically effective amount of the CENPE inhibitor to the patient.

[0016] The invention also provides a computational model useful for identifying a cancer patient suitable for treatment with a CENPE inhibitor, such as GSK923295A.

[0017] In some embodiments, the cancer is breast cancer and the cancer patient is a breast cancer patient. In certain embodiments, the breast cancer patient is a CENPE -positive breast cancer patient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The foregoing aspects and others will be readily appreciated by the skilled artisan from the following description of illustrative embodiments when read in conjunction with the accompanying drawings.

[0019] Figure 1 shows the sensitivity (-logl0(GI₅₀) to GSK923295A for 50 breast cancer cell lines classified as luminal, basal A, basal B or non-malignant human mammary epithelial. The cell lines on the left side of the graph are more sensitive to GSK923295A with GI50 more than lμM. The basal B type cells are all more sensitive to GSK923295A, where the sensitivity status is evaluated using the method of the present invention. The cell lines on the right side of the graph are more resistant to GSK923295A with GI50 more than lμM. The luminal cell type cells tended to be more resistant to GSK923295A.

[0020] Figure 2 is a graph that shows that GSK923295A induces cell apoptosis in breast cancer cells. The apoptosis rate was assessed by automatic imaging analysis system with YoPro-1 and H33342 staining after breast cancer cells treated with 2OnM, 5OnM GSK923295A for 24h, 48h and 72h.

[0021] Figure 3 shows the Caspase3 activity detected by Caspase3 GIo Assay after exposure to CENPE inhibitor, GSK923295A for 24h, 48h, and 72h.

DETAILED DESCRIPTION

[0022] Before the present invention is described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0023] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0025] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a gene" includes a plurality of such genes, and so forth. [0026] These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.

[0027] Centromere-associated protein E (CENPE) is a kinesin-like motor protein which accumulates in the G2 phase of the cell cycle and then is degraded at the end of mitosis. CENPE is responsible for mitotic chromosomal alignments and the mitotic spindle check point. GSK923295A is a small molecule inhibitor targeting CENP-E.

[0028] We describe here analyses of molecular responses to GSK923295A, a small molecule Centromere-associated protein E (CENPE) inhibitor with potential anti-neoplastic activity. GSK923295A is an inhibitor of CENPE kinesin motor domain. In Wood KW, Lad L, Luo L, Qian X, Knight SD, Nevins N, Brejc K, Sutton D, Gilmartin AG, Chua PR, Desai R, Schauer SP, McNulty DE, Annan RS, Belmont LD, Garcia C, Lee Y, Diamond MA, Faucette LF, Giardiniere M, Zhang S, Sun CM, Vidal JD, Lichtsteiner S, Cornwell WD, Greshock JD, Wooster RF, Finer JT, Copeland RA, Huang PS, Morgans DJ Jr, Dhanak D, Bergnes G, Sakowicz R, Jackson JR, "Antitumor activity of an allosteric inhibitor of centromere-associated protein-E., " Proc Natl Acad Sci USA. 2010 Feb 18. [Epub ahead of print] and hereby incorporated by reference, GSK923295 was identified as an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and the inhibitor binding site was mapped to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint.

[0029] GSK923295A is an N-(4-(imidazo[l ,2A]pyridin-YL)phenethyl)benzamide inhibitor of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases. It is contemplated that the present sets of biomarkers would predict response in other structurally similar compounds or compounds having the same mode of action. Various compounds and methods of synthesis of GSK923295A and other compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are described in the following and are hereby incorporated by reference in their entirety: U.S. Patent No. 7,504,413, U.S. Published Pat. Appl. US20090312365 and WO/2005/107762, WO/2007/056056, WO/2007/056078, WO/2007/056143, WO/2007/056469.

[0030] In the present Examples, we measured cellular responses to GSK923295A in a panel of 50 well characterized breast cell lines. Predictive biomarkers of response to GSK923295A treatment were discovered by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK923295A. Validation of these candidate predictive biomarkers will be carried out and could be used to enrich patient populations for potential responders prior to initiating therapy in the clinic and to define tailored therapeutics for individual patients.

[0031] Thus, because it is contemplated that CENPE is targeted in various human cancers, the present predictive markers can be predictive of prognosis and/or predictive of response to CENPE inhibitors used in treatment of various human cancers including but not limited to cancers such as breast, ovarian, cervical, gynecological, prostate, colon, pancreatic, squamous cell, small lung cell, lung, epithelial, basal cell, melanoma, sarcomas, carcinomas, and gliomas. In one embodiment, the cancer is an epithelial cancer such as breast, ovarian, cervical, prostate, colon, melanoma or pancreatic cancer.

[0032] In particular, individual breast cancers vary in the way they respond to molecularly targeted therapies because they vary in the spectrum of genomic, biological and epigenomic abnormalities accumulated during progression to the malignant state. The panel of 50 breast cancer cell lines has been previously found to mirror the recurrent abnormalities found in primary tumors as well as the variability therein. Therefore, molecular predictors of response to targeted therapies in patients should be the same as those that predict change in growth rate, apoptosis and/or change in cell cycle distribution in cell lines grown in vitro. Thus, while the present Examples show poor and sensitive response indicators to GSK923295A found in a panel of 50 breast cell lines, it is contemplated that these indicators can be used molecular predictors of response to targeted therapies and identifying patients predicted have poor and sensitive response to GSK923295A.

[0033] The present Examples and measured responses to GSK923295A are also contemplated to be applicable to other similar compounds that target mitotic kinesins such as CENPE. In one embodiment, the predictive gene markers should be predictive of sensitivity to other protein kinase inhibitors including substituted N-phenethylbenzamide compounds and compositions, such as N-(4-(imidazo[l,2A]pyridin-YL)phenethyl)benzamide as described by Qian et al. in U.S. Patent No. 7,504,413, and U.S. Published Pat. Appl. US20090312365, both which are hereby incorporated by reference. In another embodiment, the predictive gene markers described herein are predictive of sensitivity to the mitotic kinesin inhibitors described in the following and are hereby incorporated by reference in their entirety: WO/2005/107762, WO/2007/056056, WO/2007/056078, WO/2007/056143, WO/2007/056469.

[0034] The following genes and sequences when detected in a patient at increased expression levels in a patient indicate a patient that will be resistant to a CENPE inhibitor:

Table 1. Resistance Predictive Markers

[0035] The following when detected in a patient at increased expression levels in a patient indicate a patient that will be sensitive to CENPE inhibitor:

Table 2. Sensitivity Predictive Markers

[0036] The invention provides for a method for identifying a cancer patient suitable for treatment with a CENPE inhibitor, comprising: (a) measuring the expression level of at least one gene selected from the group consisting of the genes encoding CACNAlD, ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), wherein an increase in the expression level or a decrease of expression of at least one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, or ZFP36L2 indicates the patient is suitable for treatment with CENPE inhibitor, such as the GSK923295A compound.

[0037] In some embodiments of the invention, the method further comprises (c) measuring the expression level of a gene encoding CENPE in a sample from the patient, and (d) comparing the expression level of the gene encoding CENPE and the expression level of the gene encoding CENPE in the normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), wherein an increase in the expression level of CENPE indicates the patient is suitable for treatment with a CENPE inhibitor, such as the GSK923295A compound.

[0038] In some embodiments of the invention, step (a) comprises measuring the expression level of at least two genes selected from the group consisting of the genes encoding CACNAlD, ANK3, ClorO4, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2 in a sample from the patient.

[0039] In some embodiments of the invention, step (a) comprises measuring the expression level of at least three genes selected from the group consisting of the genes encoding CACNAlD, ANK3, ClorO4, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, or ZFP36L2 in a sample from the patient.

[0040] In some embodiments of the invention, step (a) comprises measuring the expression level of at least four genes selected from the group consisting of the genes encoding CACNAlD, ANK3, ClorO4, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, or ZFP36L2 in a sample from the patient.

[0041] The expression level of a gene is measured by measuring the amount or number of molecules of mRNA or transcript in a cell. The measuring can comprise directly measuring the mRNA or transcript obtained from a cell, or measuring the cDNA obtained from an mRNA preparation thereof. Such methods of extracting the mRNA or transcript from a cell, or preparing the cDNA thereof are well known to those skilled in the art. In other embodiments, the expression level of a gene can be measured by measuring or detecting the amount of protein or polypeptide expressed, such as measuring the amount of antibody that specifically binds to the protein in a dot blot or Western blot. The proteins described in the present invention can be overexpressed and purified or isolated to homogeneity and antibodies raised that specifically bind to each protein. Such methods are well known to those skilled in the art.

[0042] The expression level of a gene is measured from a sample from the patient that comprises essentially a cancer cell or cancer tissue of a cancer tumor. Such methods for obtaining such samples are well known to those skilled in the art. When the cancer is breast cancer, the expression level of a gene is measured from a sample from the patient that comprises essentially a breast cancer cell or breast cancer tissue of a breast cancer tumor.

[0043] The cancer patient is either a patient who is known to be CENPE-positive, that is, overexpresses the CENPE protein, or is not known whether patient is CENPE-positive or not. When the patient is not known whether to be CENPE-positive or not, the CENPE status of the patient is to be determined. [0044] In some embodiments, the method further comprises measuring the expression level of CENPE of the patients in order to determine whether the patient is an CENPE-positive patient. Methods of assaying for CENPE protein (SEQ ID NO:2) overexpression include methods that utilize immunohistochemistry (IHC) and methods that utilize fluorescence in situ hybridization (FISH). A commercially available IHC test is PathVysion® (Vysis Inc., Downers Grove, 111.). A commercially available FISH test is DAKO HercepTest® (DAKO Corp., Carpinteria, Calif). The expression level of a gene encoding CENPE can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:58.

[0045] The human homo log of CENPE protein is Centrosome-associated protein E is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle, and known as Homo sapiens centromere protein E, 312kDa (CENPE), mRNA, GenBank Accession No: NM OOl 813.2 GI :71061467 and having the nucleotide sequence and designated as SEQ ID NO:58. The CENPE protein is designated as SEQ ID NO: 156, GenBank Accession Number NP 001804.2 GL71061468, may be detected using techniques known in the art

[0046] In one embodiment, the expression level of a gene encoding protein can be measured using an oligonucleotide derived from the nucleotide sequences of SEQ ID NOS: 1-110. In another embodiment, a protein selected from one of SEQ ID NOs: 111-220 can be detected and protein levels measured using techniques as known in the art and described herein.

[0047] In some embodiments of the invention, the nucleotide sequence of a suitable fragment of the gene is used, or an oligonucleotide derived thereof. The length of the oligonucleotide of any suitable length. A suitable length can be at least 10 nucleotides, 20 nucleotides, 50 nucleotides, 100 nucleotides, 200 nucleotides, or 400 nucleotides, and up to 500 nucleotides or 700 nucleotides. A suitable nucleotide is one which binds specifically to a nucleic acid encoding the target gene and not to the nucleic acid encoding another gene.

[0048] In one embodiment, an increase in the expression level of EGFR in the patient sample, as compared to the expression level of EGFR in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is sensitive to treatment with a CENPE kinase inhibitor. [0049] A decrease in the expression level of one or more of CACNAlD, ANK3, ClorO4, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, or ZNF652 in the patient sample, as compared to the expression level of each gene in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is sensitive to treatment with the a CENPE kinase inhibitor. In some embodiments, a decrease in the expression levels of any one, two, three or four or more of 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, or ZFP36L2 in the patient sample, as compared to the expression level of each gene in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is resistant to treatment with a CENPE kinase inhibitor.

[0050] An increase in the expression level of a gene in the patient sample, as compared to the expression level of a gene in a normal tissue sample, and a modulation in the expression level of one or more of the following genes, CACNAlD, ANK3, ClorO4, C20orfl 1, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, or ZNF652 in the patient sample, as compared to the expression level of each gene in the normal tissue sample, indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is resistant to treatment with a CENPE kinase inhibitor. In some embodiments, decrease in the expression levels of any one, two, three or four of CACNAlD, ANK3, Clorf34, C20orfl 1, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, or ZNF652 in the patient sample, as compared to the expression level of each gene in a normal tissue sample, indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is sensitive to treatment with a CENPE kinase inhibitor.

[0051] When the cancer is breast cancer, the cancer cell, tissue or tumor is a breast cancer cell, tissue or tumor, respectively.

[0052] A modulation in the expression level of a gene in a patient sample selected from the genes CACNAlD, ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, COX6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, or ZNF652 and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, or ZFP36L2 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein increase of expression of one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, and ZFP36L2, and/or a decrease in the expression of one gene selected from the group consisting of CACNAlD, ANK3, ClorO4, C20orfl 1, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, or ZNF652 indicates a patient that is sensitive to a CENPE kinase inhibitor. In another embodiment, a modulation in the expression level of a gene in a patient sample selected from the genes 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL 18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, S0RBS3, TNFSF5IP1, UBE2L3, WNT5A, and ZFP36L2 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein decrease of expression of one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, S0RBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2, and/or an increase in the expression of one gene selected from the group consisting of CACNAlD, ANK3, ClorO4, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RH0BTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, indicates a patient that is resistant to a CENPE kinase inhibitor. For example, an increase in the expression level of the EGFR gene in a patient sample; and (b) comparing the expression level of EGFR from the patient with the expression level of EGFR in a normal tissue sample, wherein increase of expression of EGFR indicates a patient that is sensitive to a CENPE kinase inhibitor. Conversely, a decrease in the expression level of the EGFR gene in a patient sample compared to the expression level of EGFR from the patient with the expression level of EGFR in a normal tissue sample, indicates a patient that is resistant to a CENPE kinase inhibitor.

[0053] In some embodiments of the invention, the method comprises: (a) measuring the expression level of one gene selected from the group consisting of the genes shown in Table 1 and 2 in a sample from the patient; and (b) determining the response of the breast cancer to a substituted benzamide CENPE kinase inhibitor using the methods described herein and using a computational model described in WO 2009/123634 and WO 2009/076551.

[0054] In another embodiment, for any new sample, the expression levels of the above genes are measured and serve as inputs to the computational model, which then predicts GI50. If GI50 is low, the sample is sensitive to a substituted benzamide CENPE kinase inhibitor, and resistant if GI 50 is high. In one embodiment, the computation model is described in WO 2009/123634, hereby incorporated by reference.

[0055] In some embodiments of the invention, the method further comprises administering a therapeutically effective amount of the CENPE kinase inhibitor to the patient. Compounds and formulations of CENPE kinase inhibitors suitable for use in the present invention, and the dosages and methods of administration thereof, are taught in Qian et al. in U.S. Patent No. 7,504,413, and U.S. Published Pat. Appl. US20090312365, both which are hereby incorporated by reference, and WO/2005/107762, WO/2007/056056, WO/2007/056078, WO/2007/056143, WO/2007/056469; and WO2007/143506, the contents of all which are incorporated by reference in their entireties.

[0056] In some embodiments of the invention, the CENPE kinase inhibitor is a substituted benzamide such as GSK923295A. In other embodiments of the invention, the substituted benzamide is a N-(4-(imidazo[l,2A]pyridin-YL)phenethyl)benzamide compound as described in U.S. Patent No. 7,504,413, and U.S. Published Pat. Appl. US20090312365, which also teach methods of administration of a substituted benzamide CENPE inhibitor to a patient.

EXAMPLE 1

[0057] In this study, we measured cellular responses to GSK923295A in a panel of 50 well characterized breast cell lines. With a three-day proliferation assay, GSK923295A inhibited cell growth with a GI50 range between 2OnM to 9μM. Most of the breast cancer cell lines (40/48) showed very low GI50 of less than 20OnM. Basal subtype breast cancer cells are sensitive to the compound with the GI50 range between 2OnM to 20OnM. The non- malignant cells are very resistant to GSK923295A with GI50 >500nM. However, the luminal subtype has a very wide range of GI50s (2OnM -200OnM). The data showing the GI50 of response to GSK923295A in cell lines is shown partially in the Figures. [0058] Predictive biomarkers of response to GSK923295A treatment were discovered by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK923295A. Functional analysis of top predictive biomarkers indicates that PBK/ AKT signaling, Ephrin receptor signaling, PTEN signaling and apoptosis signaling pathways involve in cellular response of GSK923295A in breast cancer cells (p<0.01). Validation of these candidate predictive biomarkers will be carried out and could be used to enrich patient populations for potential responders prior to initiating therapy in the clinic and to define tailored therapeutics for individual patients.

[0059] The dose response curves for GSK923295 A in a panel of 50 breast cancer cell lines can be measured using the method as described in WO 2009/076551 and WO 2009/123634, which are hereby incorporated in its entirety by reference. The response curves are used to estimate the GI₅₀ value for each cell line, which are then used to perform the correlative analyses for sensitivity prediction. To identify the computational model and the predictive markers of sensitivity to GSK923295A, from cell-line panel, a training set of 30 cell-lines are randomly selected, which are used for further to learn the molecular markers and the computational model for sensitivity prediction. The remaining 10 cell-lines are used to test the accuracy of the model.

[0060] Genome-wide correlation of mRNA levels with the measured GI50 values are performed to identify statistically significant mRNA markers, (see Table 3). The cell lines found sensitive to GSK923295A are found in Figure 2.

[0061] We performed the correlative analysis using adaptive linear splines. Adaptive linear splines proceed by searching for optimal partitions in the parameter space, characteristic of multiple classes, and fitting a linear model within each partition. The fitted function is continuous, resulting in a single optimization problem. Thus, adaptive splines can simultaneously account for class information and magnitude of response in a single framework. Briefly, the response data is expressed as a sum of linear splines, where the predictor variable is the specific molecular profile of the candidate marker. For a fixed number of knots, which define the partitions, the algorithm enumeratively searches for the best location of knots by minimizing the residual sum of squares. A central challenge in predicting response in small N (cell-lines), large P (predictors) problems, is that the noise can be very strong leading to over-fitting problems. We controlled for this by using leave-one-out cross-validation (LOOCV). We also used LOOCV to determine the optimal model size, i.e. the number of knots. Goodness of fit was assessed by computing the/?-value corresponding to an F-statistic. Finally, we made sure that the selected predictor genes are consistently significant across multiple resamplings of the cell line dataset.

[0062] Table 3. Genes that correlate with predicted response to GSK923295 A.

EXAMPLE 2

[0063] Cell viability/proliferation was evaluated by CellTiter-Glo^® luminescent cell viability assay (CTG, Promega), and cell apoptosis was assayed using YoPro-1 and Hoechst staining. All cellular measurements were made in adhered cells using the Cellomics high content scanning instrument. All assays were run at 3, 4, 5 and 6 days post transfection.

[0064] Cell growth analysis was carried out using the CcllTiter-GIo ^" Luminescent Cell Viability A.vsay (Promega Cat#G7571/2/3). The luminescence signal of viable cells as measured the amount of ATP detected in the plates were read using a custom plate reader and program.

[0065] BrdU Staining and Fixation for Cellomics were used to measure cell proliferation and cell cycle analysis. To incorporate BrdU and fix the cells lOuM final concentration of BrdU (Sigma #B5002) was added directly to cell media and pulsed for 30 minutes in tissue culture incubator. The media was removed and the cells washed 2X with IX PBS and then 70% EtOH added to cover cells and fix for overnight at 4⁰C. Next day the 70% EtOH was removed and cells allowed to dry. Then 2N HCl was added and cells incubated at room temperature for 5-10 minutes, then removed and IX PBS added to neutralize. Diluted anti- BrdU antibody (Mouse anti-BrdU Clone 3D4 (BD Pharmingen #555627)) 1 :100 in IX PBS/0.5% Tween-20. Anti-BrdU was added to cells (50ul - 96 well plate; 200ul - 24 well plate) and incubated for 45-60 minutes at room temperature on a rocker. Antibody was aspirated and cells washed 2X with IX PBS/0.5% Tween-20. Rabbit Anti-mouse Alexa Fluor 488 (Invitrogen #A-11059) was diluted 1 :250 in IX PBS/0.5% Tween-20. Secondary antibody was added to cells and incubated 30-60 minutes at room temperature on a rocker then washed 3X with IX PBS/0.5% Tween-20. After the last wash was removed and cells were incubated with lug/ml Hoechst 33342 (Sigma #B2261) diluted in IX PBS for 45 minutes at room temperature on a rocker. Cells were washed and covered with IX PBS. Plates were scanned or stored at 4⁰C for later scanning on Cellomics.

[0066] YoPro-1 Staining for Cellomics was used for cell apoptosis analysis. Add YoPro- 1 (Final use at 1 ug/ml) and Hoechst (Final use at 10 ug/ml) directly to cell media. Place in 37 ⁰C incubator for 30 min. Then read directly on Cellomics. Figure 2 shows breast cancer cell viability measured by CellTiter-Glo® Luminescent Cell Viability Assay of selected cell lines after exposure to GSK923295A for 24h, 48h, and 72h. The cell lines MDAMB231, SUM52PE, and HCC 1954 exhibit reduced cell viability of 40% or less at least 72 hours after exposure to CENPE inhibitor, GSK923295A.

[0067] Figure 3 shows the Caspase3 activity detected by Caspase3 GIo Assay (Fig3) after exposure to CENPE inhibitor, GSK923295A for 24h, 48h, and 72h. The cell lines MDAMB231, SUM52PE, HCC 1954 and HBLlOO exhibit increased caspase3 activity of up to 5- fold after exposure to 2OnM or 5OnM CENPE inhibitor, GSK923295A for 72 hours.

[0068] Based on the foregoing, it was shown that GSK923295A can inhibit cell growth, induce cell apoptosis in sensitive breast cancer cells. GSK923295A is more sensitive in cell lines representing clinically aggressive basal B breast cancers sub-type than in luminal subtypes.

[0069] We identified features of genes associated with drug response and found the network major nodes to be EGFR, ERBB3, MAPKl, ESRl, PGR, CCNDl, CDKNlB,histone H3, tropomyosin, MARCKS, SH3GLB1, PKN, PRKCZ.

[0070] Using network and pathway analyses of genes associated with predictive biomarkers, We identified that PI3K/AKT signaling, Ephrin receptor signaling, PTEN signaling and apoptosis signaling pathways are involved in cellular response of GSK923295A in breast cancer cells (p<0.01) The enriched major pathways and p-values in response to GSK923295A were:

• PI3K/AKT signaling (0.001)

• Ephrin receptor signaling (0.002)

• PTEN signaling (0.01)

• Apoptosis signaling (0.01)

EXAMPLE 3 [0071] The mRNA expression levels of these genes in Glaxo SmithKline's tumor panel is obtained, and applied to a model described to predict sensitivity status of these tumors. Furthermore, the CENPE positive tumors (CENPE expression level relative to GAPDH are stratified as sensitive if predicted less than the log(GIso); others are considered resistant. The progression free survival of these predicted responders (sensitive) are compared to the non- responders (resistant). Based on the cellular response measured in the 50 breast cell line panel in Example 1 , median survival is expected to be longer for the predicted responders who are treated with GSK923295A, and shorter when treated with placebo.

[0072] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

[0073] Any references made to publications, patents, patent applications, and publicly available sequences and GenBank Accessions, are hereby incorporated by reference in their entirety for all purposes.

Claims

[0074] WE CLAIM:

1. A method for identifying a CENPE -positive cancer patient suitable for treatment with a CENPE kinase inhibitor, comprising: (a) measuring the expression level of one gene selected from the group consisting of the genes encoding CACNAlD, ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RHOBTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, and 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample or a reference expression level.

2. The method of claim 1, further comprising (c) measuring the expression level of a gene in a sample from the patient, and (d) comparing the expression level of the gene in the normal tissue sample or a reference expression level, or the average expression level in a panel of normal cell lines or cancer cell lines, whereby an increase of expression of one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPLl 8, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2 indicates the patient is suitable for treatment with a CENPE kinase inhibitor and an increase of expression of one gene selected from the group consisting of the genes encoding CACNAlD, ANK3, ClorO4, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RH0BTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, and ZNF652 indicates the patient will be resistant to treatment with a CENPE kinase inhibitor.

3. The method of claim 1, wherein step (a) comprises measuring the expression level of two genes selected from the listed group of genes in a sample from the patient.

4. The method of claim 3, wherein step (a) comprises measuring the expression level of three genes selected from from the listed group of genes in a sample from the patient.

5. The method of claim 4, wherein step (a) comprises measuring the expression level of four genes selected from the listed group of genes in a sample from the patient.

6. The method of claim 5, wherein step (a) comprises measuring the expression levels of the genes encoding CENPE and EGFR in a sample from the patient.

7. The method of claim 1 , wherein the cancer is breast cancer.

8. The method of claim 1, further comprising administering a therapeutically effective amount of a CENPE kinase inhibitor to the patient.

9. .The method of claim 8, wherein the CENPE kinase inhibitor is a substituted benzamide.

10. The method of claim 9, wherein the CENPE kinase inhibitor is a substituted N- phenethylbenzamide compound.

11. The method of claim 9, wherein the CENPE kinase inhibitor is N-(4- (imidazo [ 1 ,2A]pyridin-YL)phenethyl)benzamide.

12. A method for identifying a cancer patient suitable for treatment with GSK923295A, comprising: (a) measuring the expression level of one gene selected from the group consisting of the genes encoding CENPE, 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2 in a sample from the patient; and (b) determining the response of the cancer to GSK923295A.

13. The method of claim 12, wherein the cancer is breast cancer.

14. The method of claim 12, wherein an increase of expression of one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2 indicates the patient is suitable for treatment with a CENPE kinase inhibitor and an increase of expression of one gene selected from the group consisting of the genes encoding CACNA1D,ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RH0BTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652indicates the patient will be resistant to treatment with a CENPE kinase inhibitor.

15. A method for identifying a cancer patient suitable for treatment with GSK923295A, comprising: (a) measuring a modulation in the expression level of a gene in a patient sample selected from the genes in Table 1 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein increase of expression of one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, and ZFP36L2 and/or a decrease in the expression of one gene selected from the group consisting of CACNA1D,ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RH0BTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652, indicates a patient that is sensitive to a CENPE kinase inhibitor.

16. The method of claim 15, wherein an increase in the expression level of the EFGR gene in a patient sample compared to the expression level of EGFR from the patient with the expression level of EGFR in a normal tissue sample, indicates a patient that is sensitive to a CENPE kinase inhibitor.

17. A method for identifying a cancer patient suitable for treatment with GSK923295A, comprising: (a) measuring modulation in the expression level of a gene in a patient sample selected from the genes in Table 1 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein decrease of expression of one gene selected from the group consisting of the genes encoding 76P, ACADM, ANXA2, ARF4, ClGALTl, Clorf48, CDC42EP3, CIBl, EEF 1B2, EFNB2, EGFR, ERALl, FHL2, GART, HIRA, IDl, IK, ILF3, KCNN4, KIAA0802 /// C21orf57, KRT5, LGMN, MALL, MIDI, MRPL18, MRPL22, MRPL40, PDGFC, PPP4R1, QKI, RAB3GAP2, RAB8A, RBM9, S100A6, SAMM50, SH2B3, SLC25A12, SNAP23, SORBS3, TNFSF5IP1, UBE2L3, WNT5A, ZFP36L2, and/or an increase in the expression of one gene selected from the group consisting of CACNA1D,ANK3, Clorf34, C20orfl l, C20orfl49, CA12, CACNG4, CDKNlB, CMKORl, C0X6A1, CXorfl2, CYFIP2, DAB2, FAIM3, FAM102A, GNAS, GREBl, H3F3A /// LOC440926 /// LOC644914, HIST1H2BD, HIST2H2BE, HNRPULl, IFT 122, IGFBP2, ISOCl, ITPKl, KCTD 13, MAPT, MEGF9, MOAPl, NELL2, PDZKl, PEBPl, PEGlO, RET, RHOB, RH0BTB3, SCUBE2, SEMA4C, SH3GLB2, SIAH2, SIDTl, SLC19A2, TFFl, ZNF587, ZNF652 indicates a patient that is resistant to a CENPE kinase inhibitor.

18. The method of claim 17, wherein a decrease in the expression level of the EGFR gene in a patient sample; and (b) comparing the expression level of EGFR from the patient with the expression level of EGFR in a normal tissue sample, wherein increase of expression of EGFR indicates a patient that is resistant to a CENPE kinase inhibitor.