WO2006110593A2 - Biological targets for the diagnosis, treatment and prevention of cancer - Google Patents

Abstract

The present invention relates to methods for detecting, diagnosing, monitoring and prognosing cancer by detecting differences in the expression of one or more, or any combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib. The present invention also relates to methods for screening and identifying compounds that modulate the expression of one or more, or any combination of such genes. The invention further relates to the use of such compounds in the prevention, treatment, management and amelioration of cancer. The methods of the invention also comprise the administration of an effective amount of one or more therapies that modulate the expression and/or activity of one or more cancer targets disclosed herein for the prevention, treatment, management and amelioration of cancer.

Description

BIOLOGICAL TARGETS FOR THE DIAGNOSIS, TREATMENT AND PREVENTION OF CANCER

[0001] This application claims benefit of U.S. Provisional Application No.

60/669,342, filed April 7, 2005, entitled "Biological Targets for the Diagnosis, Treatment and Prevention of Cancer," and U.S. Provisional Application No. 60/725,982, filed October 11, 2005, entitled "Targets for the Diagnosis, Treatment and Prevention of Cancer," each of which is incoporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

[0002] The present invention relates to methods for detecting, diagnosing, monitoring and prognosing various types of cancer, including but not limited to, cancer of the colon, lung, ovary, prostate, pancreas and bladder. The methods of the invention comprise detecting differences in the expression of one or more, or any combination of the following cancer targets: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib. Such methods include, but are not limited to, detecting the relative abundance of the protein products encoded by such genes in cancer cells relative to normal cells. The present invention also relates to methods for screening and identifying compounds including, but not limited to, antibodies that modulate the expression of one or more, or any combination of the targets listed above. The invention further relates to the use of such compounds in the prevention, treatment, management and amelioration of cancer. The methods of the invention also comprise the administration of an effective amount of one or more therapies that modulate the expression and/or activity of one or more cancer targets disclosed herein for the prevention, treatment, management and amelioration of cancer.

2. BACKGROUND OF THE INVENTION 2.1. CANCER

[0003] A neoplasm, or tumor, is a neoplastic mass resulting from abnormal uncontrolled cell growth which can be benign or malignant. Benign tumors generally remain localized. Malignant tumors are collectively termed cancers. The term "malignant" generally means that the tumor can invade and destroy neighboring body structures and spread to distant sites to cause death (for review, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68-122). Cancer can arise in many sites of the body and behave differently depending upon its origin. Cancerous cells destroy the part of the body in which they originate and then spread to other part(s) of the body where they start new growth and cause more destruction.

[0004] More than 1.2 million Americans develop cancer each year. Cancer is the second leading case of death in the United States and, if current trends continue, cancer is expected to be the leading cause of the death by the year 2010. Lung and prostate cancer are the top cancer killers for men in the United States. Lung and breast cancer are the top cancer killers for women in the United States. One in two men in the United States will be diagnosed with cancer at some time during his lifetime. One in three women in the United States will be diagnosed with cancer at some time during her lifetime. [0005] A cure for cancer has yet to be found. Current treatment options, such as surgery, chemotherapy and radiation treatment, are often either ineffective or present serious side effects. Thus, there remains an urgent and continuing need to new and more effective diagnostic and therapeutic approaches to address this disease.

2.1.1 LUNG CANCER

[0006] Lung cancer is the second most frequent cancer, accounting for over 170,000 newly diagnosed patients and 157,000 deaths annually in the U.S. It is also one of the most lethal tumor types accounting for 28% of all cancer deaths (Wingo, P. A. et al. Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 91, 675-90 (1999)). Survival of patients with non-small cell carcinoma depends primarily on patient age, pathologic stage, and resectability. The impact of chemotherapy on survival has been minimal (Group, N.-s.C.L.C.C. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311, 899-909 (1995); and Souquet, PJ. et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet 342, 19-21 (1993)).

[0007] Therapeutic targeting of molecules mediating angiogenesis, cell adhesion, and growth factor signal transduction holds considerable promise for this disease, but clinical trial data are preliminary and the number of such therapeutics still limited. Candidate therapies under evaluation include monoclonal antibodies directed to cell surface molecules, most notably members of the epidermal growth factor receptor family (EGFR, HER2/neu, ErbB-3, and ErbB-4), which are over-expressed in almost all cases of squamous cell carcinoma and a majority of large cell and adenocarcinomas of the lung (Baselga, J. & Albanell, J. Targeting epidermal growth factor receptor in lung cancer. Curr Oncol Rep 4, 317-24 (2002)). [0008] Identifying additional plasma membrane proteins that are selectively expressed (or relatively over-expressed) in lung cancer would potentially provide new targets for the development of additional therapeutics, and in particular, monoclonal antibodies.

2.1.2 PROSTATE CANCER

[0009] Carcinoma of the prostate is now the most commonly diagnosed noncutaneous malignancy detected in men. Estimates from the American Cancer Society indicate that more than 198,000 American men will be diagnosed with prostate cancer. The incidence of latent, or incidental, prostate cancer approaches 35% in men over the age of 50 years which translates to an astounding 10 million affected (Hutchison, G.B. Epidemiology of prostatic cancer. Semin Oncol 3, 151-9 (1976); and Haenszel, W. & Kurihara, M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst 40, 43-68 (1968)). There remains a marked heterogeneity of disease progression among the different pathologic tumor grades and stages including the very early stage tumors now being diagnosed with the advent of widespread PSA screening. Unfortunately, there are no reliable pathological criteria or diagnostic markers that can be used to predict a clinical phenotype and thus facilitate therapeutic decisions (Montie, J.E. Current prognostic factors for prostate carcinoma. Cancer 78, 341-4 (1996)). [0010] There is great controversy regarding optimal management for early stage prostate cancers. Epidemiological studies have shown that most men with these early stage cancers managed early may have overall survivals which do not differ statistically from men of similar ages without prostate cancer (Jones, G.W. Prospective, conservative management of localized prostate cancer. Cancer 70, 307-10 (1992); and Fleming, C, Wasson, J.H., Albertsen, P. C, Barry, MJ. & Wennberg, J.E. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes Research Team. Jama 269, 2650-8 (1993)). However, a substantial number of these cancers do progress to impact survival. Therapeutic recommendations span the spectrum of expectant management, so called "watchful waiting", to radical prostatectomy or external radiotherapy. Although radical prostatectomy significantly reduces disease-specific mortality over watchful waiting, overall survival remains unchanged (Holmberg, L. et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347, 781- 9 (2002)). Despite the curative intent of prostatectomy and radiotherapy, approximately 30% of patients treated in such a fashion will relapse within 5-10 years of treatment (Walsh, P.C., Partin, A. W. & Epstein, J.I. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 152, 1831-6 (1994); Zagars, G.K. Serum PSA as a tumor marker for patients undergoing definitive radiation therapy. Urol Clin North Am 20, 737-47 (1993); and Smitt, M.C. & Heltzel, M. The results of radical prostatectomy at a community hospital during the prostate specific antigen era. Cancer 77, 928-33 (1996)) and in a Swedish study (Aus, G., Hugosson, J. & Norlen, L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 154, 460-5 (1995)), and as many as 63% of conservatively treated men who lived longer than 10 years eventually died of prostate cancer. Clearly, early stage prostate cancer is simultaneously over-treated and under-treated due to a lack of fundamental knowledge of prostate cancer biology, and a lack of biomarkers that can accurately indicate prognosis or be used as targets for treatment.

2.1.3 OVARIAN CANCER

[0011] According to the American Cancer Society, an estimated 22,220 new cases of ovarian cancer are expected in 2005 (American Cancer Society. Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society, 2005). The predicted number of deaths for 2005 is 16,210, making ovarian cancer the leading cause of death from gynecologic disease. Present survival rates for patients with ovarian cancer are unacceptably low (a five-year survival rate of less than 20% (Ries LAG, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK: SEER Cancer Statistics Review, National Cancer Institute, 1999)), owing to a combination of two fundamental factors. First, the majority of patients (>70%) are diagnosed at stage III or later, a fact that has spurred a quest for new ovarian cancer diagnostics. Second, and more importantly, effective treatments for ovarian cancer, in particular, late- stage ovarian cancer, are still lacking. Recent improvements in treatment strategies, particularly the introduction of the combination of taxanes with platinum compounds, have positively influenced ovarian cancer survival rates. Nonetheless, only a very modest decline in mortality has been observed in the years following this innovation. Advances in survival will therefore depend on both the development of more accurate screening techniques capable of detecting early disease, and the development of new paradigms for the treatment of ovarian cancer.

[0012] The urgent need for improved treatments for this patient population has prompted the development and testing of a variety of new therapeutic approaches. In general, these investigational therapies stem from the concept of targeting pathways and/or proteins with widespread roles in cancer. These include growth factors and their receptors (EGFR, p53, ErbB-2 and similar targets), signal transduction molecules, and molecules related to the cell cycle. These new approaches utilize small molecule antagonists, chemokines and immunotherapy (see HT, Kavanagh JJ: Novel agents in epithelial ovarian cancer. Cancer Invest 2004, 22 Suppl 2:29-44). In addition, various gene therapy approaches are being investigated (Kirby TO, Curiel DT, Alvarez RD: Gene therapy for ovarian cancer: progress and potential. Hematol Oncol Clin North Am 2003, 17:1021-1050). Among the investigational immunotherapeutic strategies, an antibody with high affinity for CAl 25 is currently in Phase 3 trials to establish its ability to prolong time-to-relapse in patients with advanced ovarian cancer (Berek JS: Immunotherapy of ovarian cancer with antibodies: a focus on oregovomab. Expert Opin Biol Ther 2004, 4:1159-1165). CA125 is a well known antigen associated with multiple cancers. While its secreted nature and the large amount of circulating CA125 make it a potentially useful diagnostic marker, these characteristics may limit its usefulness as a therapeutic target.

[0013] A systematic, comprehensive approach to the discovery of novel molecular targets for ovarian cancer intervention is long overdue. Most recent research has depended upon transcript-based methods such as cDNA microarrays or serial analysis of gene expression (SAGE). These methods are attractive because they can quickly survey genome- wide gene expression in a large number of samples. Such experiments have led to the identification of several promising transcripts with overexpression in ovarian carcinomas (Hough CD, Sherman-Baust CA, Pizer ES, Montz FJ, Im DD, Rosenshein NB, Cho KR, Riggins GJ, Morin PJ: Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res 2000, 60:6281-6287; Martoglio AM, Tom BD, Starkey M, Corps AN, Charnock- Jones DS, Smith SK: Changes in tumorigenesis- and angiogenesis-related gene transcript abundance profiles in ovarian cancer detected by tailored high density cDNA arrays. MoI Med 2000, 6:750-765; Ismail RS, Baldwin RL, Fang J, Browning D, Karlan BY, Gasson JC, Chang DD: Differential gene expression between normal and tumor-derived ovarian epithelial cells. Cancer Res 2000, 60:6744-6749; Welsh JB, Zarrinkar PP, Sapinoso LM, Kern SG, Behling CA, Monk BJ, Lockhart DJ, Burger RA, Hampton GM: Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci USA 2001, 98:1176-1181; Schummer M, Ng WV, Bumgarner RE, Nelson PS, Schummer B, Bednarski DW, Hassell L, L. BR, Karlan BY, Hood L: Comparative hybridization of an array of 21 500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. Gene 1999, 238:375-385; Wang K, Gan L, Jeffrey E, Gayle M, Gown AM, Skelly M, Nelson PS, Ng W, Schummer M, Hood L, Mulligan J: Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray. Gene 1999, 229:101-108). However, studies directly comparing mRNA and cognate protein have demonstrated that message level is a poor predictor of protein level in tissues (Chen G, Gharib TG, Huang CC, Taylor JM, Misek DE, Kardia SL, Giordano TJ, Iannettoni MD, Orringer MB, Hanash SM, Beer DG: Discordant protein and mRNA expression in lung adenocarcinomas. MoI Cell Proteomics 2002, 1 :304-313; Anderson L, Seilhamer J: A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 1997, 18:533-537; Gygi SP, Rochon Y, Franza BR, Aebersold R: Correlation between protein and mRNA abundance in yeast. MoI Cell Biol 1999, 19:1720-1730). Furthermore, assessment of variations in message levels cannot address the full range of variability in the tissue proteome introduced by splicing alternatives and post-translational modifications that ultimately define the state of the tissue. These observations underscore the limitations and the modest success rate of these genetic approaches in unveiling useful new therapeutic targets. They also heighten the importance of quantifying variations of not just mRNA, but also of proteins in order to understand the molecular underpinnings of a given pathological state.

2.1.4 COLON CANCER

[0014] The American Cancer Society estimates that about 104,950 new cases of colon cancer (48,290 men and 56,660 women) will be diagnosed in 2005 (American Cancer Society. Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society, 2005). Current treatments available for colorectal cancer, which includes cancer of the colon, involve surgery, radiation therapy and chemotherapy, and the type of treatment used will depend on the particular stage of colon cancer assessed in the patient. The urgent need for improved treatments for this patient population has prompted the development and testing of a variety of new therapeutic approaches, including targeted therapies using monoclonal antibodies. However, there remains a continuing need for new and more effective methods to identify targets that are associated with colon cancer in order to develop effective therapeutic approaches to treat this patient population.

2.1.5 PANCREATIC CANCER

[0015] The American Cancer Society estimates that 32,180 Americans (16,100 men and 16,080 women) will be diagnosed with cancer of the pancreas in 2005 (American Cancer Society. Cancer Facts and Figures 2005. Atlanta, GA: American Cancer Society, 2005). It is estimated at 31,800 Americans (15,820 men and 15,980 women) will die of pancreatic cancer in 2005, making it the fourth leading cause of cancer death overall. In addition, only about 23% of patients with cancer of the exocrine pancreas will be alive one year after their diagnosis, and only 4% will live five years after diagnosis. Even for those diagnosed with local disease (i.e., where the cancer has not spread to other organs), the five-year relative survival rate is approximately 15%. Currently, the three main types of treatment for pancreatic cancer are surgery, radiation therapy and chemotherapy. Due to their ineffectiveness and attendant side effects, however, there remains a continuing need for new and more effective therapeutic approaches to treat this patient population.

3. SUMMARY OF THE INVENTION

[0016] The present invention in based, in part, on the inventors' discovery that certain genes and their expression products (e.g., their protein products) are associated with cancer. In particular, the invention is based, in part, on the inventors' discovery that these genes are differentially expressed (e.g., altered, overexpressed or underexpressed) in certain types of cancers compared to normal tissue. Such cancers include, but are not limited to, cancers of the colon, lung, ovary, prostate, pancreas and bladder. The present invention provides a method for detecting, diagnosing, monitoring and/or prognosing cancer in a subject, the method comprising detecting in said subject or sample from said subject the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGCl 5668, MGC33486, TMEMl 6F, FAT, KIAAO 195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA83O, KIAA1244, KIAA1797, MGC26856, NET02, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. See, e.g., Table 1, infra. Such methods for detecting, diagnosing, monitoring and/or prognosing cancer include, for example, measuring the amount of proteins (e.g., cell surface proteins) present on cancer cells relative to normal cells. [0017] In certain embodiments, the methods for detecting, diagnosing, monitoring and/or prognosing cancer in a subject do not include the detection of the expression level of the NGEP gene and/or the UKP-Ib gene.

[0018] In a specific embodiment, cancer is detected or diagnosed by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range or a corresponding sample from a normal subject or a population of normal subjects: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In another embodiment, the stage of cancer (e.g., benign, malignant or metastatic cancer) in a subject is detected or diagnosed by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from the subject relative to a predetermined reference range or a corresponding sample from a normal subject or a population of normal subjects: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In another embodiment, the development or progression of cancer is monitored by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range or a corresponding control sample: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In accordance with this embodiment, the control sample may be obtained from a normal subject, a population of normal subjects, or the same subject at an earlier time point, hi yet another embodiment, the prognosis for a subject predisposed to or with cancer is determined by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range or a corresponding sample from a normal subject or a population of normal subjects: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot- blot, RT-PCR or ICAT-MS/MS) or an assay well-known to one of skill in the art. [0019] In specific embodiments, colon cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, 0R4M1 and/or KIAAl 679. In other specific embodiments, colon cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a colon sample from a subject relative to a predetermined reference range or a colon sample from a normal subject or a population of normal subjects: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEMl 6F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orβ, SDFRl, FLJ20481, LENG4, 0R4M1 and/or KIAAl 679. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot- blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art. [0020] In specific embodiments, lung cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ12443, FLJ20481, LENG4, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1 and/or GRIA4. In other specific embodiments, lung cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a lung sample from a subject relative to a predetermined reference range or an ovary sample from a normal subject or a population of normal subjects: TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ12443, FLJ20481, LENG4, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1 and/or GRIA4. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[0021] In specific embodiments, ovarian cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: TM9SF4, DC2, XTP3TPB, TACSTD2, FNDC3A, GKOOl, PRO1855, C20orf3, SDFRl, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14or£27, OSAP and/or FAD 104. In other specific embodiments, ovarian cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a ovary sample from a subject relative to a predetermined reference range or a lung sample from a normal subject or a population of normal subjects: TM9SF4, DC2, XTP3TPB, TACSTD2, FNDC3A, GKOOl, PRO1855, C20orf3, SDFRl, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP and/or FAD104. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[0022] In specific embodiments, prostate cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or both of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: TM9SF4, DC2, VAPB, TACSTD2, FNDC3A, GKOOl, SDFRl, ARP5 Long, ARP5 Short, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797 and/or MGC26856. In other specific embodiments, prostate cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or both of the following genes in a prostate sample from a subject relative to a predetermined reference range or a prostate sample from a normal subject or a population of normal subjects: TM9SF4, DC2, VAPB, TACSTD2, FNDC3A, GKOOl, SDFRl, ARP5 Long, ARP5 Short, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797 and/or MGC26856. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[0023] In certain embodiments, the methods for detecting, diagnosing, monitoring and/or prognosing cancer in a subject do not include the detection of the expression level of NGEP and UKP-Ib RNA or protein.

[0024] In specific embodiments, pancreatic cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of the TMD0645 gene in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample. In other specific embodiments, pancreatic cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of the TMD0645 gene in a pancreas sample from a subject relative to a predetermined reference range or a bladder sample from a normal subject or a population of normal subjects. In accordance with these embodiments, the expression of such gene is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[0025] In specific embodiments, bladder cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level of the UPK-Ib gene in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample. In other specific embodiments, bladder cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level of the UPK-Ib gene in a bladder sample from a subject relative to a predetermined reference range or a bladder sample from a normal subject or a population of normal subjects. In accordance with these embodiments, the expression of such gene is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art. [0026] In certain embodiments, the methods for detecting, diagnosing, monitoring and/or prognosing bladder cancer in a subject do not include the detection of the expression of the UPK-Ib gene.

[0027] The methods for detecting, diagnosing, monitoring and/or prognosing cancer can be used to determine the efficacy of a therapy intended to prevent, treat, manage or ameliorate cancer or a symptom thereof. In one embodiment, the efficacy of a therapy for a subject predisposed to or with cancer is evaluated or predicted by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding sample from a normal subject, or a subject or population of subjects in which the therapy has had a therapeutic effect: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. Monitoring the influence of a therapy (e.g., an agent) on the expression or activity of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAAl 679 and/or UPK-Ib gene products {e.g., mRNA and/or protein products) can, therefore, be applied in basic drug screening, preclinical studies, clinical trials and during therapeutic regimens designed to treat, manage or ameliorate cancer or a symptom thereof.

[0028] The expression level of the SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2,

C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib genes can be measured at the RNA and/or protein level. In a preferred embodiment, the expression level of such genes is measured at the protein level. [0029] In instances wherein the amount of SLC 12A2, FLJ23375, GRM5, TAS2R1 ,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib mRNA or protein in a sample {e.g., a colon, lung, ovary prostate and/or pancreas sample) from a subject is greater (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75% greater, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold greater) than that of the predetermined reference range or a corresponding negative control sample (e.g., a colon, lung, ovary prostate and/or pancreas sample from a normal subject or a population of normal subjects), such a result indicates that the subject has cancer. Such a result may also indicate the effectiveness of the therapy being administered to the subject. [0030] In instances wherein the amount of SLC12A2, FLJ23375, GRM5, TAS2R1 ,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib mRNA or protein in a sample (e.g., a colon, lung, ovary prostate and/or pancreas sample) from subject is less (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75% less, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold less) than or equal to that of the predetermined reference range or corresponding control sample from a normal subject or a population of normal subjects, or a subject or population of subjects prior to the administration of a therapy (e.g., a colon, lung, ovary prostate and/or pancreas sample), such a result indicates that the subject does not have cancer, the health of the subject is improving (e.g., the cancer is not spreading or growing as quickly as it was or the cancer is regressing), or the effectiveness of the therapy being administered to the subject. Such a result may also indicate the stage of the cancer.

[0031] The methods for detecting, diagnosing, monitoring and/or prognosmg cancer described herein can further comprise techniques well-known to those of skill in the art for the detection, diagnosis, monitoring and/or prognosis of the stage or grade of cancer. For example, the methods described herein may further comprise performing x-rays, computed tomography, magnetic resonance imaging (MRI), and PSA tests.

[0032] The present invention provides methods of identifying compounds that bind to

SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGCl 5668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib nucleic acid or amino acid sequences. The present invention also provides methods for identifying compounds that modulate the expression and/or activity of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib nucleic acid or amino acid sequences. The compounds identified via such methods are useful for the development of animal models to study cancer. Further, the compounds identified via such methods are useful as lead compounds in the development of prophylactic and therapeutic compositions for the prevention, treatment, management and/or amelioration of cancer or a symptom thereof. Such methods are particularly useful in that the effort and great expense involved in testing potential prophylactics and therapeutics in vivo is efficiently focused on those compounds identified via the in vitro and ex vivo methods described herein.

[0033] The present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a cell expressing a gene product of a gene described herein (e.g., an mRNAor protein encoded by a gene described herein) or gene product fragment (e.g., a fragment of an mRNA or protein) of a gene described herein with a test compound; and (b) determining the ability of the test compound to bind to the gene product or gene product fragment, so that if a compound binds to the gene product or gene product fragment, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In a specific embodiment, the assay comprises contacting a cell which expresses a gene product or gene product fragment of a gene described herein with a known compound which binds the gene product or gene product fragment to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with the gene product or gene product fragment, wherein determining the ability of the test compound to interact with the gene product or gene product fragment comprises determining the ability of the test compound to preferentially bind to the gene product or gene product fragment as compared to the known compound. [0034] The present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a gene product or a fragment thereof of a gene described herein with a test compound; and (b) determining the ability of the test compound to bind to the gene product or gene product fragment so that if a compound binds to the gene product or gene product fragment, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In a specific embodiment, the assay includes contacting a gene product or gene product fragment of a gene described herein with a known compound which binds the gene product or gene product fragment to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with the gene product or gene product fragment, wherein determining the ability of the test compound to interact with the gene product or gene product fragment comprises determining the ability of the test compound to preferentially bind to the gene product or gene product fragment as compared to the known compound. [0035] The present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a cell expressing a gene product(s) or a fragment thereof of a gene described herein with a test compound; (b) determining the amount of the gene product(s) or gene product fragment(s) present in (a); and (c) comparing the amount(s) in (a) to that/those present in a corresponding control cell that has not been contacted with the test compound, so that if the amount of the gene product(s) or gene product fragment(s) is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In a specific embodiment, the expression level(s) is altered by 5%, 10%, 15%, 25%, 50%, or 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at lease 4 fold, at least 5 fold, at least 10 fold or at least 25 fold relative to the expression level in the control sample as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art. In certain embodiments, such a method comprises determining the amount of a gene product or fragment thereof of at least two, at least three, or all of the genes present in the cell and comparing the amounts to those present in the control. [0036] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell (e.g., a colon, lung, ovary, prostate or pancreas cell) expressing a gene product or fragment thereof of a gene described herein with a test compound; (b) determining the amount of the gene product or gene product fragment present in (a); and (c) comparing the amount in (a) to that present in a corresponding control cell that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the expression of a gene product or fragment thereof of at least one, at least two or all of the genes described herein, present in the cell (e.g., a colon, lung, ovary, prostate or pancreas cell) and comparing the amounts to those present in the control. In specific embodiments, the expression level(s) is decreased by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well-known to one of skill in the art.

[0037] The present invention also provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell-free extract with a nucleic acid sequence comprising a nucleotide sequence encoding a gene product or fragment thereof of a gene described herein and test compound; (b) determining the amount of at least one of the gene product or gene fragment present in (a); and (c) comparing the amount(s) in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In specific embodiments, the expression level(s) is altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold relative to the expression level in the control as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT-PCR) or an assay well known to one of skill in the art. In alternate embodiments, such a method comprises determining the amount of a gene product or fragment thereof of at least two, at least three, or all of the genes described herein present in the extract and comparing the amounts to those present in the control. [0038] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell-free extract with a nucleic acid sequence comprising a nucleotide sequence encoding a gene product or fragment thereof of a gene product described herein and a test compound; (b) determining the amount of the gene product or gene product fragment present in (a); and (c) comparing the amount in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the expression of a gene product or fragment thereof of at least one, at least two or all of the of the genes described herein, present in the extract and comparing the amounts to those present in the control, hi specific embodiments, the expression level(s) is decreased by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT- PCR) or an assay well-known to one of skill in the art.

[0039] Standard methods for determining the amount of a gene product or fragment thereof of a gene described herein can be utilized. In specific embodiments, RT-PCR and dot-blotting methods are used to determine the amount of an RNA transcript of a gene described herein in a sample.

[0040] In preferred embodiments, isotope-coded affinity tag (ICAT) quantitative protein profiling by tandem mass spectometry (ICAT-MS/MS) is used to determine the amount of protein encoded by a gene described herein in a sample. In accordance with these embodiments, the proteins detected are enriched in the plasma membrane of cancer cells or cancer tissues (e.g., colon, lung, ovarian, prostate, pancreatic and/or bladder cancer cells or tissues), i.e., their expression is increased in the plasma membrane of cancer cells or cancer tissues of a subject (e.g., colon, lung, ovarian, prostate, pancreatic and/or bladder cancer cells or tissues) relative to corresponding control cells or tissues from a normal subject or population of normal subjects. In certain embodiments, the amount of nucleic acid (e.g., mRNA transcript) encoding the proteins or fragments thereof detected by the methods of the present invention do not correlate with the amount of proteins or fragments thereof detected. [0041] The present invention provides methods of identifying compounds to be tested for their ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, comprising methods for identifying compounds that modulate the activity of a gene product (e.g., protein of a gene described herein). Such methods can comprise: (a) contacting a cell expressing a gene product of at least one gene described herein with a test compound; (b) determining the activity of the gene product; and (c) comparing the activity level or levels to that in a corresponding control cell that has not been contacted with the test compound, so that if the level of activity of the gene product in (a) is altered relative to the level of activity in the control sample, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In specific embodiments, the activity level(s) is altered by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold relative to the activity level in the control sample as determined by utilizing an assay described herein or an assay well-known to one of skill in the art. In alternate embodiments, such a method comprises determining the activity level of a gene product of at least two, at least three, or all of the genes described herein present in the cell and comparing the activity levels to those present in the control.

[0042] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell (e.g., a colon, lung, ovary, prostate or pancreas cell) expressing a gene product of a gene described herein with a test compound; (b) determining the activity of of the gene product; and (c) comparing the activity level to that present in a corresponding control cell that has not been contacted with the test compound, so that if the activity level of the gene product is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the activity level of a gene product of at least one, at least two or all of the genes described herein, present in the cell and comparing the activity levels to those present in the control.

[0043] The present invention provides methods of identifying compounds to be tested for their ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, comprising: (a) contacting a cell-free extract with a nucleic acid comprising a nucleotide sequence encoding a gene product or fragment thereof of a gene described herein and a test compound; (b) determining the activity of the gene product or gene product fragment; and (c) comparing the activity level to that in a corresponding control that has not been contacted with the test compound, so that if the level of the gene product or gene product fragment activity in (a) is altered relative to the level of activity in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In alternate embodiments, such a method comprises determining the activity level of at least two, at least three, or all of the genes described herein present in the extract and comparing the activity levels to those present in the control.

[0044] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell-free extract (e.g., colon, lung, ovary, prostate or pancreas cell extract) with a nucleic acid sequence comprising a nucleotide sequence encoding a gene product or fragment thereof of a gene described herein and a test compound; (b) determining the activity level of the gene product or gene product fragment; and (c) comparing the activity level in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the activity level of the gene product or gene product fragment is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the activity level of a gene product or fragment thereof of at least one, at least two or all of genes described herein, present in the extract and comparing the activity levels to those present in the control.

[0045] The compounds utilized in the assays described herein may be members of a library of compounds. In specific embodiment, the compound is selected from a combinatorial library of compounds comprising peptoids; random biooligomers; diversomers such as hydantoins, benzodiazepines and dipeptides; vinylogous polypeptides; nonpeptidal peptidomimetics; oligocarbamates; peptidyl phosphonates; peptide nucleic acid libraries; antibody libraries; carbohydrate libraries; and small organic molecule libraries. In a preferred embodiment, the small organic molecule libraries are libraries of benzodiazepines, isoprenoids, thiazolidinones, metathiazanones, pyrrolidines, morpholino compounds, or diazepindiones. In another specific embodiment, the compounds utilized in the assays described herein are antibodies, preferably monoclonal antibodies that are specific to a gene product or fragment thereof of a gene described herein.

[0046] In certain embodiments, the compounds are screened in pools. Once a positive pool has been identified, the individual compounds of that pool are tested separately. In certain embodiments, the pool size is at least 2, at least 5, at least 10, at least 25, at least 50, at least 75, at least 100, at least 150, at least 200, at least 250, or at least 500 compounds. [0047] Once a compound that modulates the expression and/or activity of one or more of the genes described herein is identified, the structure of the compound may be determined utilizing well-known techniques or by referring to a predetermined code. For example, the structure of the compound may be determined by mass spectroscopy, NMR, vibrational spectroscopy, or X-ray crystallography.

[0048] In certain embodiments of the invention, the compound identified using the assays described herein is a cell surface protein, e.g., a. receptor. In a preferred embodiment, the compound identified using the assays described herein is not known to affect the expression and/or activity of a gene product of one or more or all of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJl 2443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In another preferred embodiment, the compound identified using the assays described herein has not been used as or suggested to be useful in prevention, treatment, management or amelioration of cancer or a symptom thereof. [0049] A compound that binds to a gene product or fragment thereof of a gene described herein modulates the expression and/or activity of a gene product of a gene described herein, may be tested in in vitro assays and/or in vivo assays well-known to one of skill in the art or described herein for the effect of said compound in biological assays such as those described herein, or any other assay well known in the art for assessing the efficacy of a compound for the prevention, treatment, management or amelioration of cancer or a symptom thereof. In a specific embodiment, a compound of the invention is an antibody, preferably a monoclonal antibody, specific for a gene product (e.g., a protein) or gene product fragment of a gene described herein.

[0050] The invention provides for methods for preventing, treating, managing or ameliorating cancer or a symptom thereof, said method comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, identified according to the methods described herein. In a specific embodiment, the invention provides for method of preventing, treating, managing or ameliorating cancer or a symptom thereof, said method comprising administering to a subject in need thereof an effective amount of an antibody specific to a gene product (e.g., a protein) or gene product fragment of a gene described herein and a pharmaceutically acceptable carrier. The invention also provides methods of preventing, treating, managing or ameliorating cancer or a symptom thereof, said methods comprising administering to a subject in need thereof one or more of the compounds identified utilizing the methods described herein, and one or more other therapies (e.g., prophylactic or therapeutic agents and/or surgery). In a specific embodiment, such therapies are currently being used, have been used or are known to be useful in the prevention, treatment, management or amelioration of cancer or a symptom thereof (including, but not limited to the prophylactic or therapeutic agents listed in Section 5.6 herein below).

[0051] The methods of the invention further comprise the administration of an effective amount of one or more therapies (e.g., prophylactic or therapeutic agents) that modulate the expression and/or activity of one or more cancer targets disclosed herein (e.g., one or more targets disclosed in Table 1, infra) for the prevention, treatment, management and amelioration of cancer. In a specific embodiment, such therapies are currently being used, have been used or are known to be useful in the prevention, treatment, management or amelioration of cancer or a symptom thereof (including, but not limited to the prophylactic or therapeutic agents listed in Section 5.6 herein below). [0052] The invention also provides pharmaceutical compositions comprising a compound identified according to the methods described herein. Such compositions are useful for the prevention, treatment, management or amelioration of cancer or a symptom thereof.

[0053] The invention further provides diagnostic kits for detecting the amount and/or presence a gene product or fragment thereof of a gene described herein in a sample, e.g., a colon, lung, ovary, prostate or pancreas sample taken from a patient or control subject.

3.1. TERMINOLOGY

[0054] As used herein, the term "analog" in the context of a proteinaceous agent (e.g. , proteins, polypeptides, peptides, and antibodies) refers to a proteinaceous agent that possesses a similar or identical function as a second proteinaceous agent but does not necessarily comprise a similar or identical amino acid sequence of the second proteinaceous agent, or possess a similar or identical structure of the second proteinaceous agent. A proteinaceous agent that has a similar amino acid sequence refers to a second proteinaceous agent that satisfies at least one of the following: (a) a proteinaceous agent having an amino acid sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the amino acid sequence of a second proteinaceous agent; (b) a proteinaceous agent encoded by a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence encoding a second proteinaceous agent of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, or at least 150 contiguous amino acid residues; and (c) a proteinaceous agent encoded by a nucleotide sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the nucleotide sequence encoding a second proteinaceous agent. A proteinaceous agent with similar structure to a second proteinaceous agent refers to a proteinaceous agent that has a similar secondary, tertiary or quaternary structure to the second proteinaceous agent. The structure of a proteinaceous agent can be determined by methods known to those skilled in the art, including but not limited to, peptide sequencing, X-ray crystallography, nuclear magnetic resonance, circular dichroism, and crystallographic electron microscopy. [0055] To determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes {e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=number of identical overlapping positions/total number of position times 100%). In one embodiment, the two sequences are the same length.

[0056] The determination of percent identity between two sequences can also be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl Acad. Sci. U.S.A. 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873-5877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. MoI. Biol. 215:403. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the present invention. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score-50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule of the present invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI- BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g. , of XBLAST and NBLAST) can be used (see, e.g., the NCBI website). Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0057] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0058] As used herein, the term "analog" in the context of a non-proteinaceous analog refers to a second organic or inorganic molecule which possess a similar or identical function as a first organic or inorganic molecule and is structurally similar to the first organic or inorganic molecule.

[0059] As used herein, the terms "antibody" and "antibodies"refer to polyclonal antibodies, monoclonal antibodies, niultispecifϊc antibodies, human antibodies, humanized antibodies, chimeric antibodies, single-chain Fvs (scFv), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope- binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding site. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGi, IgG2, IgG3, IgGφ IgAi ^and Ig A2) or subclass. In a specific embodiment, the antibodies of the invention bind to any one of the following proteins or fragments thereof: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. [0060] As used herein, the term "cancer" refers to a disease involving cells that have the potential to metastasize to distal sites and exhibit phenotypic traits that differ from those of non-cancer cells, for example, formation of colonies in a three-dimensional substrate such as soft agar or the formation of tubular networks or weblike matrices in a three-dimensional basement membrane or extracellular matrix preparation, such as MATRIGEL™. Non-cancer cells do not form colonies in soft agar and form distinct sphere-like structures in three- dimensional basement membrane or extracellular matrix preparations. Cancer cells acquire a characteristic set of functional capabilities during their development, albeit through various mechanisms. Such capabilities include evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion/metastasis, limitless replicative potential, and sustained angiogenesis. The term "cancer cell" is meant to encompass both pre- malignant and malignant cancer cells.

[0061] As used herein, the terms "compound" and "agent" are used interchangably.

[0062] As used herein, the term "derivative" in the context of proteinaceous agent

(e.g., proteins, polypeptides, peptides, and antibodies) refers to a proteinaceous agent that comprises an amino acid sequence which has been altered by the introduction of amino acid residue substitutions, deletions, and/or additions. The term "derivative" as used herein also refers to a proteinaceous agent which has been modified, i.e., by the covalent attachment of any type of molecule to the proteinaceous agent. For example, but not by way of limitation, a proteinaceous agent may be modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. A derivative of a proteinaceous agent may be produced by chemical modifications using techniques known to those of skill in the art, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Further, a derivative of a proteinaceous agent may contain one or more non-classical amino acids. A derivative of a proteinaceous agent possesses a similar or identical function as the proteinaceous agent from which it was derived.

[0063] As used herein, the term "derivative" in the context of a non-proteinaceous derivative refers to a second organic or inorganic molecule that is formed based upon the structure of a first organic or inorganic molecule. A derivative of an organic molecule includes, but is not limited to, a molecule modified, e.g., by the addition or deletion of a hydroxyl, methyl, ethyl, carboxyl or amine group. An organic molecule may also be esterified, alkylated and/or phosphorylated. [0064] As used herein, the term "diagnosis" refers to a process of determining if an individual is afflicted with cancer or for determining the grade or stage of cancer. In this context, "diagnosis" refers to a process whereby one increases the likelihood that an individual is properly characterized as being affilicted with a cancer or a grade or stage of cancer ("true positive") or is properly characterized as not being afflicted with cancer or a grade or stage of cancer ("true negative") while minimizing the likelihood that the individual is improperly characterized as being afflicted with cancer or a grade or stage or cancer ("false positive") or improperly characterized as not being afflicted with cancer or a grade or stage of cancer ("false negative").

[0065] As used herein, the term "effective amount" in the context of administering a therapy refers to the amount of a compound which is sufficient to reduce or ameliorate the progression, severity and/or duration of cancer or one or more symptoms thereof, prevent the development, recurrence or onset of cancer or one or more symptoms thereof, prevent the advancement or spread of cancer or one or more symptoms thereof, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. In other embodiments, the term "effective amount" in the context of diagnosis is the amount of a compound which is sufficient to detect a gene product or gene product fragment of a gene of interest (e.g., a gene described herein). For example, an effective amount of an antibody is that amount of an antibody sufficient to immunospecifically bind to and detect a protein of interest in a tissue or cell of interest.

[0066] The term "epitopes" as used herein refers to a fragment of an SLCl 2 A2,

FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein having antigenic or immunogenic activity in an animal, preferably in a mammal, and most preferably in a mouse or a human. An epitope having immunogenic activity is a fragment of an SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein that elicits an antibody response in an animal. An epitope having antigenic activity is a fragment of an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein to which an antibody immunospecifically binds as determined by any method well known in the art, for example, by immunoassays. Antigenic epitopes need not necessarily be immunogenic. [0067] As used herein, the term "fragment" refers to a peptide or polypeptide comprising an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues of the amino acid sequence of another polypeptide or a protein. In a specific embodiment, a fragment of a protein or polypeptide retains at least one function of the protein or polypeptide. In another embodiment, a fragment of a protein or polypeptide retains at least two, three, four, or five functions of the protein or polypeptide. Preferably, a fragment of an antibody retains the ability to immunospecifically bind to an antigen.

[0068] As used herein, the term "functional fragment" refers to a peptide or polypeptide comprising an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues of the amino acid sequence of second, different polypeptide, wherein said peptide or polypeptide retains at least one function of the second, different polypeptide.

[0069] As used herein, the term "fusion protein" refers to a polypeptide that comprises an amino acid sequence of a first protein or polypeptide or functional fragment, analog or derivative thereof, and an amino acid sequence of a heterologous protein, polypeptide, or peptide (i.e., a second protein or polypeptide or fragment, analog or derivative thereof different than the first protein or fragment, analog or derivative thereof). In one embodiment, a fusion protein comprises a prophylactic or therapeutic agent fused to a heterologous protein, polypeptide or peptide. In accordance with this embodiment, the heterologous protein, polypeptide or peptide may or may not be a different type of prophylactic or therapeutic agent.

[0070] As used herein, the term "gene product" refers to the biochemical products of expression of a particular gene or gene of interest (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib). Genes are transcribed into segments of RNA (ribonucleic acid), which are translated into proteins. Both RNA and proteins are products of the expression of the gene and, in some cases, can be quantified to determine the activity of the gene. In certain embodiments, abnormal amounts of gene product may be associated with the presence of a disease-causing mutation and/or disease. In a specific embodiment, a gene product is a cell surface protein. As used herein, the term "gene product fragment" refers to any fragment of a gene product that may contain the whole gene product or less than all of the gene product. Such a gene product fragment may or may not be biologically active. In certain embodiments, the gene product fragment may have constitutive activity; dominant negative activity or no apparent activity. In a specific embodiment, a gene product fragment is a fragment of a cell surface protein.

[0071] As used herein, the term "hybridizes under stringent conditions" describes conditions for hybridization and washing under which nucleotide sequences at least 30% (preferably, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 98%) identical to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. In one, non-limiting example stringent hybridization conditions are hybridization at 6 x sodium chloride/sodium citrate (SSC) at about 45° C, followed by one or more washes in 0.1 x SSC, 0.2% SDS at about 68° C. In a preferred, non-limiting example stringent hybridization conditions are hybridization in 6 x SSC at about 45° C,followed by one or more washes in 0.2.X.SSC, 0.1% SDS at 50-65° C (i.e., one or more washes at 50° C, 55° C, 60° C or 65° C). It is understood that the nucleic acids of the invention do not include nucleic acid molecules that hybridize under these conditions solely to a nucleotide sequence consisting of only A or T nucleotides. [0072] As used herein, the term "immunospecifically binds to an antigen" and analogous terms refer to peptides, polypeptides, proteins, fusion proteins and antibodies or fragments thereof that specifically bind to an antigen and do not specifically bind to other antigens. A peptide, polypeptide, protein, or antibody that immunospecifically binds to an antigen may bind to other peptides, polypeptides, or proteins with lower affinity as determined by, e.g., immunoassays, BIAcore, or other assays known in the art. For example, antibodies or fragments that immunospecifically bind to an antigen may cross-reactive with related antigens. Preferably, antibodies or antibody fragments that immunospecifically bind to an antigen do not cross-react with other antigens.

[0073] As used herein, the term "in combination" refers to the use of more than one therapy (e.g., prophylactic and/or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with cancer. A first therapy (e.g., a prophylactic or therapeutic agent) can be administered prior to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g, a prophylactic or therapeutic agent) to a subject which had, has, or is susceptible to cancer. The therapies (e.g., prophylactic or therapeutic agents) are administered to a subject in a sequence and within a time interval such that the therapy of the invention can act together with the other therapy to provide an increased benefit than if they were administered otherwise. Any additional therapy (e.g., prophylactic or therapeutic agent) can be administered in any order with the other additional therapies (e.g., prophylactic or therapeutic agents).

[0074] As used herein, the terms "isolated" in the context of a compound other than a nucleic acid molecule or proteinaceous agent, e.g., a compound identified in accordance with the method of the invention, refer to a compound that is substantially free of chemical precursors or other chemicals when chemically synthesized, hi a specific embodiment, the compound is 60%, preferably 65%, 70%, 75%, 80%, 85%, 90%, or 99% free of other, different compounds. In a preferred embodiment, a compound identified in accordance with the methods of the invention is purified. [0075] As used herein, the term "isolated" in the context of a proteinaceous agent

(e.g., a peptide, polypeptide, fusion protein or antibody) refers to proteinaceous agent which is substantially free of cellular material or contaminating proteins from the cell or tissue source from which it is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of a proteinaceous agent in which the proteinaceous agent is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, a proteinaceous agent that is substantially free of cellular material includes preparations of a proteinaceous agent having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous proteinaceous agent (also referred to herein as a "contaminating protein"). When the proteinaceous agent is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. When the proteinaceous agent is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the proteinaceous agent. Accordingly such preparations of a proteinaceous agent have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the proteinaceous agent of interest. In a preferred embodiment, an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib peptide, polypeptide or fragment thereof is isolated.

[0076] As used herein, the term "isolated" in the context of nucleic acid molecules refers to a nucleic acid molecule which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. In a preferred embodiment, a nucleic acid molecule encoding SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib is isolated.

[0077] As used herein, the phrase "low tolerance" refers to a state in which the patient suffers from side effects from therapy so that the patient does not benefit from and/or will not continue the therapy because of the adverse effects and/or the harm from the side effects outweighs the benefit of the therapy.

[0078] As used herein, the terms "manage", "managing" and "management" refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent) which does not result in a cure of cancer. In certain embodiments, a subject is administered one or more therapies to "manage" cancer so as to prevent the progression or worsening of the cancer.

[0079] As used herein, the phrase "non-responsive/refractory" is used to describe patients treated with one or more currently available therapies (e.g., cancer therapies) such as chemotherapy, radiation therapy, surgery, hormonal therapy and/or biological therapy/immunotherapy, particularly a standard therapeutic regimen for the particular cancer, wherein the therapy is not clinically adequate to treat the patients such that these patients need additional effective therapy, e.g., remain unsusceptible to therapy. The phrase can also describe patients who respond to therapy yet suffer from side effects, relapse, develop resistance, etc. In various embodiments, "non-responsive/refractory" means that at least some significant portion of the cancer cells are not killed or their cell division arrested. The determination of whether the cancer cells are "non-responsive/refractory" can be made either in vivo or in vitro by any method known in the art for assaying the effectiveness of treatment on cancer cells, using the art-accepted meanings of "refractory" in such a context. In various embodiments, a cancer is "non-responsive/refractory" where the number of cancer cells has not been significantly reduced, or has increased during the receipt of the therapy. [0080] As used herein, "normal" refers to an individual who has not shown any cancer symptoms or has not been diagnosed with cancer. "Normal", according to the invention, also refers to a sample taken from normal individuals within 14 hours postmortem. A normal tissue sample, for example, refers to the whole or a piece of a tissue isolated from, for example, prostate, ovary, lung, colon, pancreas or bladder tissue within 14 hours post-mortem from an individual who was not diagnosed with cancer and whose corpse does not show any symptoms of cancer at the time of tissue removal. In certain embodiments of the invention, the "normal" tissue sample is isolated from a subject less than 14 hours postmortem, e.g., within 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, S hours, 4 hours, 3 hours, 2 hours, or 1 hour post-mortem. In one embodiment of the invention, the "normal" tissue sample is isolated at 14 hours post-mortem and the integrity of mRNA and/or protein samples extracted is confirmed.

[0081] As used herein, the terms "non-responsive" and refractory" describe patients treated with a currently available therapy {e.g., prophylactic or therapeutic agent) for cancer, which is not clinically adequate to relieve one or more symptoms associated therewith. Typically, such patients suffer from severe, persistently active disease and require additional therapy to ameliorate the symptoms associated with their cancer.

[0082] As used herein, the terms "nucleic acids" and "nucleotide sequences" include

DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), combinations of DNA and RNA molecules or hybrid DNA/RNA molecules, and analogs of DNA or RNA molecules. Such analogs can be generated using, for example, nucleotide analogs, which include, but are not limited to, inosine or tritylated bases. Such analogs can also comprise DNA or RNA molecules comprising modified backbones that lend beneficial attributes to the molecules such as, for example, nuclease resistance or an increased ability to cross cellular membranes. The nucleic acids or nucleotide sequences can be single-stranded, double-stranded, may contain both single-stranded and double-stranded portions, and may contain triple-stranded portions, but preferably is double-stranded DNA. [0083] As used herein, the phrase "pharmaceutically acceptable salt(s)," includes, but is not limited to, salts of acidic or basic groups that may be present in compounds identified using the methods of the present invention. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium lithium, zinc, potassium, and iron salts.

[0084] As used herein, the term "population" in context of subjects refers to 2 or more, preferably 5 or more, 10 or more, 25 or more, 50 or more, 100 or more, 150 or more, 200 or more, 250 or more, 300 or more, or 500 or more subjects.

[0085] As used herein, the term "potentiate" refers to an improvement in the efficacy of a therapeutic agent at its common or approved dose.

[0086] As used herein, the terms "prevent", " preventing" and "prevention" refer to the prevention of the development, recurrence, onset or spread of cancer or one or more symptoms thereof resulting from the administration of one or more compounds identified in accordance the methods of the invention or the administration of a combination of such a compound and another therapy.

[0087] As used herein, the term "previously determined reference range" refers to a reference range for the expression and/or activity of a gene in a subject or population of subjects, a sample from a subject or a population of subjects in a particular assay. It is preferred that each laboratory establish its own reference range for each particular assay, each tissue type, each cell type and each type of cell-free extract. In a preferred embodiment, at least one positive control and at least one negative control are included in each batch of compounds analyzed. [0088] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any compound(s) which can be used in the prevention of cancer. In certain embodiments, the term "prophylactic agent" refers to a compound identified in the screening assays described herein. In certain other embodiments, the term "prophylactic agent" refers to an agent other than a compound identified in the screening assays described herein which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development and/or progression of cancer or one or more symptoms thereof. [0089] As used herein, the phrase "prophylactically effective amount" refers to the amount of a therapy (e.g. , a prophylactic agent) which is sufficient to result in the prevention of the development, recurrence, spread or onset of cancer or one or more symptoms thereof. [0090] A used herein, a "protocol" includes dosing schedules and dosing regimens.

[0091] As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a prophylactic or therapeutic agent. Adverse effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a prophylactic or therapeutic agent might be harmful or uncomfortable or risky. Side effects from chemotherapy include, but are not limited to, gastrointestinal toxicity such as, but not limited to, early and late-forming diarrhea and flatulence, nausea, vomiting, anorexia, leukopenia, anemia, neutropenia, asthenia, abdominal cramping, fever, pain, loss of body weight, dehydration, alopecia, dyspnea, insomnia, dizziness, mucositis, xerostomia, and kidney failure, as well as constipation, nerve and muscle effects, temporary or permanent damage to kidneys and bladder, flu-like symptoms, fluid retention, and temporary or permanent infertility. Side effects from radiation therapy include but are not limited to fatigue, dry mouth, and loss of appetite. Side effects from biological therapies/immunotherapies include but are not limited to rashes or swellings at the site of administration, flu-like symptoms such as fever, chills and fatigue, digestive tract problems and allergic reactions. Side effects from hormonal therapies include but are not limited to nausea, fertility problems, depression, loss of appetite, eye problems, headache, and weight fluctuation. Additional undesired effects typically experienced by patients are numerous and known in the art. Many are described in the Physicians' Desk Reference (59^th ed., 2005).

[0092] As used herein, the term "small molecules" and analogous terms include, but are not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds. [0093] As used herein, the terms "subject" and "patient" are used interchangeably to refer to an animal (e.g., a mammal, a fish, an amphibian, a reptile, a bird and an insect). In a specific embodiment, a subject is a mammal (e.g., a non-human mammal and a human). In another embodiment, a subject is a pet (e.g., a dog, a cat, a guinea pig, a monkey and a bird), a farm animal (e.g., a horse, a cow, a pig, a goat and a chicken) or a laboratory animal (e.g., a mouse and a rat). In another embodiment, a subject is a primate (e.g., a chimpanzee and a human). In a preferred embodiment, a subject is a human.

[0094] As used herein, the term "synergistic" refers to a combination of a compound identified using one of the methods described herein, and another therapy (e.g., agent), which is more effective than the additive effects of the therapies. Preferably, such other therapy has been or is currently being to prevent, treat, manage or ameliorate cancer or a symptom thereof. A synergistic effect of a combination of therapies (e.g., prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with cancer. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said agent to a subject without reducing the efficacy of said therapies in the prevention, treatment, management or amelioration of cancer. In addition, a synergistic effect can result in improved efficacy of therapies (e.g., agents) in the prevention, treatment, management or amelioration of cancer. Finally, a synergistic effect of a combination of therapies (e.g., prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[0095] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any compound(s) which can be used in the treatment, management or amelioration of cancer or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" refers to a compound identified in the screening assays described herein. In other embodiments, the term "therapeutic agent" refers to an agent other than a compound identified in the screening assays described herein which is known to be useful for, or has been or is currently being used to treat, manage or ameliorate cancer or one or more symptoms thereof.

[0096] As used herein, a "therapeutically effective amount" refers to that amount of the therapeutic agent sufficient to destroy, modify, control or remove primary, regional or metastatic cancer tissue. A therapeutically effective amount may refer to the amount of therapeutic agent sufficient to delay or minimize the spread of cancer. A therapeutically effective amount may also refer to the amount of the therapeutic agent that provides a therapeutic benefit in the treatment or management of cancer. Further, a therapeutically effective amount with respect to a therapeutic agent of the invention means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of cancer. Used in connection with an amount of an therapeutic agent of the invention, the term can encompass an amount that improves overall therapy, reduces or avoids unwanted effects, or enhances the therapeutic efficacy of or synergies with another therapeutic agent. Preferably, a therapeutically effective of a therapy (e.g., a therapeutic agent) reduces the progression of cancer by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% relative to a control such as phosphate buffered saline ("PBS").

[0097] As used herein, the terms "treat," "treating" and "treatment" refer to the eradication, reduction or amelioration of cancer or a symptom thereof, particularly, the eradication, removal, modification, or control of primary, regional, or metastatic cancer tissue that results from the administration of one or more therapies. In certain embodiments, such terms refer to the minimizing or delaying the spread of cancer resulting from the administration of one or more therapies to a subject with cancer.

4. BRIEF DESCRIPTION OF THE FIGURE

[0098] FIG. 1. Methods for Identifying Cancer Targets. This figure outlines exemplary methods used to identify potential cancer targets that are differentially expressed in certain types of cancer. 5. DETAILED DESCRIPTION OF THE INVENTION

[0099] The present invention in based, in part, on the inventors' discovery that certain genes and their expression products (e.g., their protein products) are associated with cancer. Such cancers include, but are not limited to, cancers of the colon, lung, ovary, prostate and pancreas. In particular, the invention is based on the inventors' discovery that these genes are differentially expressed (e.g., altered, overexpressed or underexpressed) in certain types of cancers compared to normal tissue. The invention is further based, in part, on the inventors' discovery that certain genes (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib) are overexpressed on the cell surface of certain types of cancer cells (e.g., cancers of the colon, lung, ovary, prostate and pancreas) relative to normal cells. Identification of the cancer-associated genes using the methods described herein provides an effective approach to define cancer targets and to develop more effective therapies such as immune-based therapies (e.g., antibodies) to treat cancer.

5.1. METHODS FOR IDENTIFYING GENES ASSOCIATED WITH CANCER

[00100] The present invention provides methods for identifying a "cancer target" gene whose expression is useful in the diagnosis of cancer and for targeting the treatment, prevention, management and/or amelioration of cancer or a symptom thereof. Such methods include the detection and/or quantification of gene products (preferably, niRNAs, and more preferably, proteins) or gene product fragments of genes of interest (preferably, a gene described herein such as SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib) that are differentially expressed in cancer subjects or samples from cancer subjects relative to normal subjects or samples from normal subjects. In a preferred embodiment, quantitative tissue proteomics (e.g., isotope-coded affinity tag (ICAT) quantitative protein profiling by tandem mass spectometry (ICAT-MS/MS)) is used to identifiy a gene that is differentially expressed in cancer subjects relative to normal subjects. [00101] In specific embodiments, the ICAT technique used in the methods of the invention enables the comparison of protein levels of two biological samples in a relatively quantitative manner (see Example 1, infra). In particular, this technique allows the direct comparison of the relative abundance of cell surface proteins on cancer cells relative to normal cells. In a specific embodiment, the method comprises a step to enrich for plasma membrane proteins by targeting glycosylated proteins. This is followed by proteolysis, isolation of tagged peptides, and mass spectrometric sequence analysis and quantification (see, Gygi et al., 1999, Nat. Biotechnol. 17:994-999, the entire contents of which are incorporated by reference herein in its entirety). This technique allows the simultaneous identification of the components of extremely complex protein mixtures together with determination of their relative abundance. In specific embodiments, analysis of proteins using the ICAT-MS/MS technique may be performed using any source of protein, including but not limited to, those harvested from body fluids, cells and/or tissues. [00102] Once a peptide from a protein is determined to be differentially expressed in cancer subjects relative to normal subjects, then genomics is applied to identify the nucleotide sequence encoding the protein. For example, available databases (e.g., GenBank) and literature are searched for proteins that comprise the peptide differentially expressed in cancer subjects relative to normal subjects and nucleotide sequences encoding proteins that comprise such a peptide. [00103] In order to validate the cancer target, techniques that measure the RNA and protein expression profiles in normal and cancer tissues are conducted. In one embodiment, RT-PCR is performed using methods well-known to those skilled in the art or using methods described herein, to validate (i.e. confirm the differential expression of) potential cancer targets (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib) identified by the ICAT-MS/MS proteomics technique and/or IHC analysis.

[00104] In specific embodiments, RNA dot blot analysis is performed using methods well-known to those skilled in the art or using methods described herein, to validate (i.e. confirm the overexpression of) potential cancer targets (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib) identified by the ICAT-MS/MS proteomics technique and/or IHC analysis. [00105] In yet other specific embodiments, once a protein(s) of interest (e.g. ,

SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib) is identified using ICAT- MS/MS, polyclonal antisera or monoclonal antisera may be raised against the protein(s) of interest using techniques well-known to those skilled in the art or described herein. Such polyclonal or monoclonal antisera may be used in immunohistochemistry (IHC) experiments using methods well-known to those skilled in the art or described herein to detect the protein(s) of interest in various tissue or cell types (e.g., in prostate, ovary, lung, colon, pancreas and/or bladder tissue or cells). In a specific embodiment, IHC experiments detect a greater amount of the protein of interest in cancer tissues or cells (e.g., prostate cancer, ovarian cancer, lung cancer, colon cancer, pancreatic cancer and/or bladder cancer) relative to normal or non-cancer tissues or cells. In another specific embodiment, once a protein(s) is identified to be overexpressed in a cancer tissue or cell relative to a normal or non-cancer tissue or cell, such a protein(s) may be considered a potential cancer target. [00106] In a specific embodiment, once a gene product or gene product fragment of a gene of interest is confirmed to be differentially expressed using expression analysis techniques such as described above, such a gene product or gene product fragment may be considered to be a potential cancer target and may be used in the methods for detecting, diagnosing, monitoring and/or prognosing cancer in a subject, described infra, hi yet other embodiments, once a gene product or gene product fragment of a gene of interest is confirmed to be differentially expressed using expression analysis techniques such as described above, compounds that target the expression and/or activity of such a gene product or gene product fragment may be identified and their utility in preventing, treating, managing and/or ameliorating cancer or a symptom thereof is assessed in in vitro and animal models for cancer.

5.2. METHODS OF DIAGNOSISING CANCER

[00107] The present invention provides a method for detecting, diagnosing, monitoring and/or prognosing cancer in a subject, the method comprising detecting the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a subject or a sample from the subject: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. See, for example, Table 1, infra. [00108] In a specific embodiment, cancer is detected or diagnosed by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range or a corresponding sample from a normal subject a population of normal subjects, individual subjects with different stages of cancer or a population of subjects with different stages of cancer: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib. In another embodiment, the stage of cancer (e.g., benign, malignant or metastatic cancer) in a subject is detected or diagnosed by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from the subject relative to a predetermined reference range, a sample from a normal subject or a population of normal subjects, or a sample from individual subjects with different stages of cancer or a population of subjects with different stages of cancer: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT-PCR) or an assay well-known in the art. [00109] In another embodiment, the development or progression of cancer is monitored by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range or a corresponding control sample: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In accordance with this embodiment, the control sample may be obtained from a normal subject, a population of normal subjects, individual subjects with different stages of cancer or a population of subjects with different stages of cancer or the same subject at an earlier time point. In yet another embodiment, the prognosis for a subject predisposed to or with cancer is determined by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range or a corresponding sample from a normal subject, a population of normal subjects, individual subjects with different stages of cancer or a population of subjects with different stages of cancer: SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT-PCR) or an assay well-known in the art. [00110] In specific embodiments, colon cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. In other specific embodiments, colon cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a colon sample from a subject relative to a predetermined reference range or a colon sample from a normal subject or a population of normal subjects: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[00111] In specific embodiments, lung cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ12443, FLJ20481, LENG4, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1 and/or GRIA4. In other specific embodiments, lung cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a lung sample from a subject relative to a predetermined reference range or an ovary sample from a normal subject or a population of normal subjects: TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ12443, FLJ20481, LENG4, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1 and/or GRIA4. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[00112] In specific embodiments, ovarian cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: TM9SF4, DC2, XTP3TPB, TACSTD2, FNDC3A, GKOOl, PRO1855, C20orf3, SDFRl, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP and/or FAD 104. In other specific embodiments, ovarian cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a ovary sample from a subject relative to a predetermined reference range or a lung sample from a normal subject or a population of normal subjects: TM9SF4, DC2, XTP3TPB, TACSTD2, FNDC3A, GKOOl, PRO1855, C20orf3, SDFRl, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP and/or FAD104. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[00113] In specific embodiments, prostate cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or more, or any combination of the following genes in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample: TM9SF4, DC2, VAPB, TACSTD2, FNDC3A, GKOOl, SDFRl, ARP5 Long, ARP5 Short, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAAl 797 and/or MGC26856. In other specific embodiments, prostate cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of one or both of the following genes in a prostate sample from a subject relative to a predetermined reference range or a prostate sample from a normal subject or a population of normal subjects: TM9SF4, DC2, VAPB, TACSTD2, FNDC3A, GKOOl, SDFRl, ARP5 Long, ARP5 Short, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797 and/or MGC26856. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by at least 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[00114] In certain embodiments, the methods for detecting, diagnosing, monitoring and/or prognosing cancer in a subject do not include the detection of the expression level of NGEP and UKP-Ib RNA or protein. [00115] In specific embodiments, pancreatic cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of the TMD0645 gene in a subject or a sample from a subject relative to a predetermined reference range, a control subject or a corresponding control sample. In other specific embodiments, pancreatic cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level, and in particular, the protein products, of the TMD0645 gene in a pancreas sample from a subject relative to a predetermined reference range or a bladder sample from a normal subject or a population of normal subjects. In accordance with these embodiments, the expression of such gene is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[00116] In specific embodiments, bladder cancer is detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level of the UPK-Ib gene in a subject or a sample from a subject relative to a predetermined reference range , a control subject or a corresponding control sample. In other specific embodiments, bladder cancer is detected, diagnosed, monitored and/or prognosed by detecting an alteration in the expression level of the UPK-Ib gene in a bladder sample from a subject relative to a predetermined reference range or a bladder sample from a normal subject or a population of normal subjects. In accordance with these embodiments, the expression of such gene is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art.

[00117] In certain embodiments, cancer is not detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level of the NGEP and/or UKPK-Ib gene in a sample from a subject relative to a predetermined reference range or a corresponding control sample. In specific embodiments, cancer is not detected, diagnosed, monitored or prognosed by detecting an alteration in the expression level of the NGEP and/or UKPK-Ib gene in a prostate or bladder sample, respectively, from a subject relative to a predetermined reference range or a prostate or bladder sample, respectively, from a normal subject. [00118] In a specific embodiment, cancer is detected or diagnosed by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the genes described herein, and the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of other genes known to be associated with cancer (including, but not limited to, HER2/NEU, PSA, BRACAl, KI-RAS, C-MYC, L-MYC, MSH2, MSH6, MLHl, ABCBl, ACVRlB, BAG3, BAG4, FGFR3, H-RAS, RBl and TB53) in a sample from a subject relative to a predetermined reference range or a corresponding sample from a normal subject a population of normal subjects, individual subjects with different stages of cancer or a population of subjects with different stages of cancer. In accordance with these embodiments, the expression of such a gene(s) is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 8 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well-known in the art. [00119] The methods for detecting, diagnosing, monitoring and prognosing cancer can be used to determine the efficacy of a therapy intended to prevent, treat, manage or ameliorate cancer or a symptom thereof. Thus, in one embodiment, the efficacy of a therapy for a subject predisposed to or with cancer is evaluated or predicted by detecting an alteration in the expression level, and in particular, the protein products, of at least 1, at least 2 or at least 3, or any combination of the following genes in a sample from a subject relative to a predetermined reference range, or a corresponding sample from a normal subject, a population of normal subjects, individual subjects with different stages of cancer, a population of subjects with different stages of cancer, a subject in which the therapy had a negative or beneficial effect, or a population of subjects in which the therapy had a negative or beneficial effect: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. Monitoring the influence of a therapy (e.g., a therapeutic or prophylactic agent) on the expression or activity of a gene product or gene product fragment of a gene described herein can, therefore, be applied in basic drug screening, preclinical studies, clinical trials and during therapeutic regimens designed to treat, manage or ameliorate cancer or a symptom thereof.

[00120] In instances wherein the amount of a gene product (e.g. , the amount of mRNA or protein or fragment thereof) of a gene described herein in a sample from a subject is greater (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75% greater, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold greater) than that of the predetermined reference range or a corresponding control colon, lung, ovary, prostate or pancreas sample (e.g., a sample of colon, lung, ovary, prostate or pancreas cells from a normal subject, a population of normal subjects, individual subjects with different stages of cancer or a population of subjects with different stages of cancer), such a result indicates that the subject has cancer. Such a result may also indicate the stage of cancer, that the cancer has progressed or the effectiveness of the therapy being administered to the subject.

[00121] In instances wherein the amount of a gene product (e.g. , mRNA or protein or fragment thereof) of a gene described herein in a sample from subject is greater (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75% less, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold less) than or equal to that of the predetermined reference range or a corresponding cancer control sample (e.g., a sample of colon, lung, ovary, prostate or pancreas cancer tissue or cells from an individual subject or population of subjects with cancer), such a result indicates that the subject has cancer. Such a result may also indicate the stage of the cancer.

[00122] In instances wherein the amount of a gene product (e.g. , mRNA or protein or fragment thereof) of a gene described herein in a cancer sample (e.g., a sample of colon, lung, ovary, prostate or pancreas cells) from a subject is less (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75% less, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold greater or equal) than that of the predetermined reference range or a corresponding control sample of the same stage of cancer (e.g., a sample of colon, lung, ovary, prostate or pancreas cancer tissue or cells from an individual subject or population of subjects with corresponding stages of cancer), such a result indicates that the subject has the same stage of cancer as that of the control cancer subjects. [00123] In instances wherein the amount of a gene product (e.g., mRNA or protein or fragment thereof) of a gene described herein in a cancer sample (e.g., a sample of colon, lung, ovary, prostate or pancreas cells) from a subject is decreased (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75% less, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold less) relative to that of the predetermined reference range or a corresponding control sample (e.g., a sample of colon, lung, ovary, prostate or pancreas cells from a normal subject, a population of normal subjects, individual subjects with different stages of cancer or a population of subjects with different stages of cancer), such a result indicates that the subject does not have cancer. Such a result may also indicate the effectiveness of the therapy being administered to the subject.

[00124] In instances wherein the amount of SLC12A2, FLJ23375, GRM5, TAS2R1,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib mRNA or protein in a cancer sample (e.g., a colon, lung, ovary, prostate or pancreas cancer sample) from a subject is decreased (preferably, 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75% less, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, or 25 fold less) or is equal relative to that of a sample from the same subject obtained before a therapy is administered (e.g., a sample of colon, lung, ovary, prostate or pancreas cancer tissue or cells from said individual before cancer therapy), such a result indicates that the cancer has regressed to a less severe stage and/or the therapy is working.

[00125] In a specific embodiment, the invention provides a method for detecting or diagnosing cancer in a subject, the method comprising: (a) determining the expression level of at least 1 of the following genes in a sample from the subject: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEMl 6F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; and (b) comparing the level of expression in (a) to a corresponding control sample from a normal subject, a population of normal subjects, individual subjects with different stages of cancer, or a population of subjects with different stages of cancer, wherein cancer is detected or diagnosed if there is an increase in the expression level of such gene in (a) relative to the expression in the control sample. [00126] In a specific embodiment, the invention provides a method for detecting or diagnosing cancer in a subject, the method comprising: (a) determining the expression level of at least 2, at least 3 or any combination of the following genes in a sample from the subject: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib; and (b) comparing the level of expression in (a) to a corresponding control sample from a normal subject, a population of normal subjects, individual subjects with different stages of cancer, or a population of subjects with different stages of cancer, wherein cancer is detected or diagnosed if there is an increase in the expression level of such gene in (a) relative to the expression in the control sample. [00127] The expression level of the SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2,

C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib genes can be measured at the RNA and/or protein level. [00128] SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668,

MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib nucleic acid and amino acid sequences are well known to those of skill in the art. See, for example, Table 1, infra, which provides the GenBank accession numbers for the nucleic acid and amino acid sequences of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib. Further, additional forms, e.g., alleles or species homologs of such sequences can routinely be obtained and detected using the sequences described above in conjunction with standard cloning and hybridization techniques such as those find in Sambrook et al., eds., Molecular

Cloning: A Laboratory Manual, 2^n<^. ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989.

Table 1

[00129] Labeled antibodies, derivatives and analogs thereof, which immunospecifically bind to a protein encoded by a gene described herein can be used for diagnostic purposes to detect, diagnose, or monitor cancer. In a specific embodiment, cancer is detected in the patient. The patient is an animal, preferably a mammal and most preferably a human.

[00130] In one embodiment, diagnosis is carried out by: (a) administering preferably, locally to an affected tissue, of a patient an effective amount of a labeled molecule which immunospecifically binds to SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; (b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate in the affected tissue in the patient (and for unbound labeled molecule to be cleared to background level); (c) determining background level; and (d) detecting the labeled molecule in the patient, such that detection of labeled molecule above the background level and above a predetermined reference range or a corresponding control indicates the presence of cancer.

[00131] The invention provides methods for the diagnosis or detection of cancer in a patient, said methods comprising imaging said animal at a time interval after administering to said patient an effective amount of a labeled antibody which immunospecifically binds to a protein encoded by a gene described, said time interval being sufficient to permit the labeled antibody to preferentially concentrate at any joint in said patient, wherein detection of the labeled antibody localized at the site in the subject above background level and above a predetermined reference range or corresponding control indicates the presence of cancer. [00132] Depending on several variables, including the type of label used and the mode of administration, the time interval following the administering for permitting the labeled molecule to preferentially concentrate at any joint in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.

[00133] Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the invention include but are not limited to: computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography. [00134] In a specific embodiment, the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S. Patent 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).

[00135] In particular embodiments, the diagnostic methods of the invention provide methods of imaging and localizing metastases and methods of diagnosis and prognosis using tissues and fluids distal to the primary tumor site (as well as methods using tissues and fluids of the primary tumor), for example, whole blood, sputum, urine, serum, fine needle aspirates (i.e., biopsies). In other embodiments, the diagnostic methods of the invention provide methods of imaging and localizing metastases and methods of diagnosis and prognosis in vivo.

[00136] The methods for detecting, diagnosing, monitoring and/or prognosing cancer described herein can further comprise techniques well-known to those of skill in the art for the detection, diagnosis, monitoring and/or prognosis of the stage or grade of cancer. For example, the methods described herein may further comprise performing x-rays, computed tomography, magnetic resonance imaging (MRI), and PSA tests. [00137] Methods for monitoring the development or progression of cancer can be performed at any point following the diagnosis of cancer. Methods for monitoring the efficacy of a therapy can also be performed at any point following the administration of a therapy. In some instances, monitoring is performed biweekly, weekly, bimonthly, monthly, biannually, yearly or every two years. It is understood, of course, that the frequency of monitoring can, at least in part, depend upon the particular situation (e.g., the severity of the cancer, overall health of the subject, the particular therapy being administered, etc.).

5.3. SOURCE OF A SAMPLE

[00138] Unless otherwise indicated herein, any tissue sample (e.g., a colon, lung, ovary prostate or pancreas sample) or cell sample (e.g., colon, lung, ovary prostate or pancreas cell sample) obtained from any subject may be used in accordance with the methods of the invention. Examples of subjects from which such a sample may be obtained and utilized in accordance with the methods of the invention include, but are not limited to, asymptomatic subjects, subjects manifesting or exhibiting 1, 2, 3, 4 or more symptoms of cancer, subjects clinically diagnosed as having cancer, subjects predisposed to cancer (e.g., subjects with a family history of cancer, subjects with a genetic predisposition to cancer, and subjects that lead a lifestyle that predisposes them to cancer or increases the likelihood of contracting cancer), subjects suspected of having cancer, subjects undergoing therapy for cancer, subjects with cancer and at least one other condition (e.g., subjects with 2, 3, 4, 5 or more conditions), subjects not undergoing therapy for cancer, subjects determined by a medical practitioner (e.g., a physician) to be healthy or cancer-free (i.e., normal), subjects that have been cured of cancer, subjects that are managing their cancer, and subjects that have not been diagnosed with cancer. In a specific embodiment, the subjects from which a sample may be obtained and utilized have cancer of the prostate, ovary, lung, colon or bladder. In another embodiment, the subjects from which a sample may be obtained and utilized have benign, malignant or metastatic cancer.

[00139] In certain embodiments, the sample obtained from a subject is a colon, lung, ovary prostate or pancreas sample (including a sample of cells from colon, lung, ovary prostate or pancreas). For example, a tissue biopsy by methods well-known to those skilled in the art may be obtained from a subject.

[00140] In certain embodiments, the sample obtained from a subject is a blood sample.

A sample of blood may be obtained from a subject having any of the following developmental or disease stages of cancer. In some embodiments, a drop of blood is collected from a simple pin prick made in the skin of a subject. In such embodiments, this drop of blood collected from a pin prick is all that is needed. Blood may be drawn from a subject from any part of the body (e.g., a finger, a hand, a wrist, an arm, a leg, a foot, an ankle, a stomach, and a neck) using techniques known to one of skill in the art, in particular methods of phlebotomy known in the art. In a specific embodiment, venous blood is obtained from a subject and utilized in accordance with the methods of the invention. In another embodiment, arterial blood is obtained and utilized in accordance with the methods of the invention. The composition of venous blood varies according to the metabolic needs of the area of the body it is servicing. In contrast, the composition of arterial blood is consistent throughout the body. For routine blood tests, venous blood is generally used. [00141] Venous blood can be obtained from the basilic vein, cephalic vein, or median vein. Arterial blood can be obtained from the radial artery, brachial artery or femoral artery. A vacuum tube, a syringe or a butterfly may be used to draw the blood. Typically, the puncture site is cleaned, a tourniquet is applied approximately 3-4 inches above the puncture site, a needle is inserted at about a 15-45 degree angle, and if using a vacuum tube, the tube is pushed into the needle holder as soon as the needle penetrates the wall of the vein. When finished collecting the blood, the needle is removed and pressure is maintained on the puncture site. Usually, heparin or another type of anticoagulant is in the tube or vial that the blood is collected in so that the blood does not clot. When collecting arterial blood, anesthetics can be administered prior to collection.

[00142] The collected sample is optionally stored at refrigerated temperatures, such 4°

C, prior to use in accordance with the methods of the invention. In some embodiments, a portion of the sample is used in accordance with the invention at a first instance of time whereas one or more remaining portions of the sample is stored for a period of time for later use. This period of time can be an hour or more, a day or more, a week or more, a month or more, a year or more, or indefinitely. For long term storage, storage methods well known in the art, such as storage at cryo temperatures {e.g. below -60 °C) can be used. In some embodiments, in addition to storage of the sampleor instead of storage of the sample, isolated nucleic acid or protein are stored for a period of time for later use. Storage of such molecular markers can be for an hour or more, a day or more, a week or more, a month or more, a year or more, or indefinitely.

[00143] In some embodiments of the present invention, cells from a tissue sample or blood sample are separated from whole tissue or whole blood are collected from a subject using techniques known in the art.

[00144] Cells from a can be sorted using a using a fluorescence activated cell sorter

(FACS). Fluorescence activated cell sorting (FACS) is a known method for separating particles, including cells, based on the fluorescent properties of the particles. See, for example, Kamarch, 1987, Methods Enzymol 151:150-165. Laser excitation of fluorescent moieties in the individual particles results in a small electrical charge allowing electromagnetic separation of positive and negative particles from a mixture. An antibody or ligand used to detect a cell antigenic determinant present on the cell surface of particular cells is labeled with a fluorochrome, such as FITC or phycoerythrin. The cells are incubated with the fluorescently labeled antibody or ligand for a time period sufficient to allow the labeled antibody or ligand to bind to cells. The cells are processed through the cell sorter, allowing separation of the cells of interest from other cells. FACS sorted particles can be directly deposited into individual wells of microtiter plates to facilitate separation. [00145] Magnetic beads can be also used to separate cells in some embodiments of the present invention. For example, cells can be sorted using a using a magnetic activated cell sorting (MACS) technique, a method for separating particles based on their ability to bind magnetic beads (0.5-100 μm diameter). A variety of useful modifications can be performed on the magnetic microspheres, including covalent addition of an antibody which specifically recognizes a cell-solid phase surface molecule or hapten. A magnetic field is then applied, to physically manipulate the selected beads. In a specific embodiment, antibodies to a cell surface marker are coupled to magnetic beads. The beads are then mixed with the cell culture to allow binding. Cells are then passed through a magnetic field to separate out cells having the cell surface markers of interest. These cells can then be isolated. [00146] In some embodiments, the surface of a culture dish may be coated with antibodies, and used to separate cells by a method called panning. Separate dishes can be coated with antibody specific to particular blood cells. Cells can be added first to a dish coated with cell specific antibodies of interest. After thorough rinsing, the cells left bound to the dish will be cells that express the cell markers of interest. Examples of cell surface antigenic determinants or markers for blood cells include, but are not limited to, CD2 for T lymphocytes and natural killer cells, CD3 for T lymphocytes, CDl Ia for leukocytes, CD28 for T lymphocytes, CD 19 for B lymphocytes,CD20 for B lymphocytes, CD21 for B lymphocytes, CD22 for B lymphocytes, CD23 for B lymphocytes, CD29 for leukocytes, CD 14 for monocytes, CD41 for platelets, CD61 for platelets, CD66 for granulocytes, CD67 for granulocytes and CD68 for monocytes and macrophages.

5.4. METHODS OF MEASURING NUCLEIC ACID SEQUENCE EXPRESSION

[00147] Any semi-quantitative or quantitative technique known to one of skill in the art may be used to measure the expression of one or more of the following genes: SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14or£27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. See, e.g., Sambrook, Fritsch & Maniatis, 1982, Molecular Cloning: A Laboratory Manual; DNA Cloning: A Practical Approach, volumes I and II (D.N. Glover ed. 1985); Oligonucleotide Synthesis Gait ed., 1984; Nucleic Acid Hybridization, Hames & Higgins eds., 1985; Transcription and Translation, Hames & Higgins eds., 1984, Animal Cell Culture, Freshney ed., 1986, Immobilized Cells And Enzymes, IRL Press, 1986, Perbal, 1984, A Practical Guide To Molecular Cloning. In a specific embodiment, the expression level of one or more of such genes is measured using a high throughput semi-quantitative technique. In another embodiment, the expression level of such genes is measured using a high throughput quantitative technique. In another embodiment, the expression level of one or more of such genes is measured using semi-quantitative and quantitative techniques. However measured, the result is either the absolute or relative amounts of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAAl 679 and/or UPK-Ib gene expression, including but not limited to values representing abundances or abundance ratios. The expression of one or more of the following genes can be measured by measuring RNA and/or protein levels: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAAOl 95, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. 5.4.1 NUCLEIC ACID DETECTION

5.4.1.1 MICROARRAYS

[00148] In one embodiment, nucleic acid arrays are employed for analyzing the expression of one or more of the following genes in a sample: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib in a sample. In a specific embodiment, an expression profile is obtained by hybridizing detectably labeled polynucleotides representing the nucleic acid sequences in mRNA transcripts present in a cell (e.g., fluorescently labeled cDNA synthesized from total cell mRNA) to a microarray comprising SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BA¹HDl, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib polynucleotides (i.e., a portion of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib DNA that is transcribed by RNA polymerase, including, but not limited to, a 5' untranslated region ("UTR"), introns, exons and a 3' UTR). In a particular embodiment, such a microarray only contains a total of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 polynucleotides other than SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NET02, SUSD2, F0LR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib polynucleotides.

[00149] Microarrays can be made in a number of ways, of which several are described herein below. Preferably microarrays are reproducible, allowing multiple copies of a given array to be produced and results from said microarrays compared with each other. Preferably, the microarrays are made from materials that are stable under binding (e.g., nucleic acid hybridization) conditions. Microarrays are preferably small, e.g., between 1 cm and 25 cm , preferably 1 to 3 cm .

[00150] Microarrays used can include one or more test probes. In some embodiments each such test probe comprises a polynucleotide sequence that is complementary to a subsequence of RNA or DNA to be detected. Each probe typically has a different nucleic acid sequence, and the position of each probe on the solid surface of the array is usually known or can be determined. Microarrays useful in accordance with the invention can include oligonucleotide microarrays, cDNA based arrays, SNP arrays, spliced variant arrays and any other array able to provide a quantitative or semi-quantitative measurement of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib gene expression. Some types of microarrays are addressable arrays. More specifically, some microarrays are positionally addressable arrays. In some embodiments, each probe of the array is located at a known, predetermined position on the solid support so that the identity (e.g., the sequence) of each probe can be determined from its position on the array (e.g., on the support or surface). In some embodiments, the arrays are ordered arrays.

[00151] In some embodiments of the present invention, an expressed transcript (e.g., a transcript of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJl 4281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib) is represented in the nucleic acid arrays. In such embodiments, a set of binding sites can include probes with different polynucleotides that are complementary to different sequence segments of the expressed transcript. Exemplary polynucleotides that fall within this class can be of length of 15 to 200 bases, 20 to 100 bases, 40-60 bases or some other range of bases. Each probe sequence can also comprise linker sequences in addition to the sequence that is complementary to its target sequence. As used herein, a linker sequence is a sequence between the sequence that is complementary to its target sequence and the surface of support. For example, in some embodiments, the nucleic acid arrays of the invention comprise one probe specific to each target gene or exon. However, if desired, the nucleic acid arrays can contain at least 2, 5, 10, 100, or 1000 or more probes specific to some expressed transcript (e.g., a transcript of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAAl 679 and/or UPK-Ib). For example, the array may contain probes tiled across the sequence of the longest mRNA isoform of a gene at single base steps.

[00152] It will be appreciated that when cDNA complementary to the RNA of a cell is made and hybridized to a microarray under suitable hybridization conditions, the level of hybridization to the site in the array corresponding to an exon of the SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib gene will reflect the prevalence in the cell of mRNA or mRNAs containing the exon transcribed from that gene. For example, when detectably labeled (e.g., with a fluorophore) cDNA complementary to the total cellular mRNA is hybridized to a microarray, the site on the array corresponding to an exon of a gene (i.e., capable of specifically binding the product or products of the gene expressing) that is not transcribed or is removed during RNA splicing in the cell will have little or no signal (e.g., fluorescent signal), and an exon of a gene for which the encoded mRNA expressing the exon is prevalent will have a relatively strong signal. The relative abundance of different mRNAs produced from the same gene by alternative splicing is then determined by the signal strength pattern across the whole set of exons monitored for the gene. [00153] In one embodiment, hybridization levels at different hybridization times are measured separately on different, identical microarrays. For each such measurement, at hybridization time when hybridization level is measured, the microarray is washed briefly, preferably in room temperature in an aqueous solution of high to moderate salt concentration (e.g., 0.5 to 3 M salt concentration) under conditions which retain all bound or hybridized polynucleotides while removing all unbound polynucleotides. The detectable label on the remaining, hybridized polynucleotide molecules on each probe is then measured by a method which is appropriate to the particular labeling method used. The resulted hybridization levels are then combined to form a hybridization curve. In another embodiment, hybridization levels are measured in real time using a single microarray. In this embodiment, the microarray is allowed to hybridize to the sample without interruption and the microarray is interrogated at each hybridization time in a non-invasive manner. In still another embodiment, one can use one array, hybridize for a short time, wash and measure the hybridization level, put back to the same sample, hybridize for another period of time, wash and measure again to get the hybridization time curve.

TARGET POLYNUCLEOTIDE MOLECULES

[00154] Target polynucleotides that can be analyzed by the methods and compositions of the invention include RNA molecules such as, but by no means limited to, expressed RNA molecules which includes messenger RNA (mRNA) molecules, mRNA spliced variants as well as other regulatory RNA, cRNA molecules (e.g., RNA molecules prepared from cDNA molecules that are transcribed in vivo) and fragments thereof. Target polynucleotides which may also be analyzed by the methods and compositions of the present invention include, but are not limited to DNA molecules such as genomic DNA molecules, cDNA molecules, and fragments thereof including oligonucleotides, ESTs, STSs, etc.

[00155] The target polynucleotide molecules may be naturally occurring nucleic acid molecules such as genomic or extragenomic DNA molecules isolated from a sample, or RNA molecules, such as mRNA molecules, isolated from a sample. The sample of target polynucleotides can comprise, e.g., molecules of DNA, RNA, or copolymers of DNA and RNA. In specific embodiments, the target polynucleotides of the invention will correspond to particular genes or to particular gene transcripts (e.g., to particular mRNA sequences expressed in specific cell types or to particular cDNA sequences derived from such mRNA sequences). The target polynucleotides may correspond to different exons of the same gene, e.g., so that different splice variants of that gene may be detected and/or analyzed. [00156] In specific embodiments, the target polynucleotides to be analyzed are prepared in vitro from nucleic acids extracted from a sample. For example, in one embodiment, RNA is extracted from a sample (e.g., total cellular RNA, poly(A)⁺ messenger RNA, fraction thereof) and messenger RNA is purified from the total extracted RNA. Methods for preparing total and poly(A)⁺ RNA are well known in the art, and are described generally, e.g., in Sambrook et al., supra. In one embodiment, RNA is extracted from a sample using guanidinium thiocyanate lysis followed by CsCl centrifugation and an oligo dT purification (Chirgwin et al., 1979, Biochemistry 75:5294-5299). In another embodiment, RNA is extracted from a sample using guanidinium thiocyanate lysis followed by purification on RNeasy columns (Qiagen). cDNA is then synthesized from the purified mRNA using, e.g., oligo-dT or random primers. In specific embodiments, the target polynucleotides are cRNA prepared from purified messenger RNA extracted from a sample. As used herein, cRNA is defined here as RNA complementary to the source RNA. The extracted RNAs are amplified using a process in which doubled-stranded cDNAs are synthesized from the RNAs using a primer linked to an RNA polymerase promoter in a direction capable of directing transcription of anti-sense RNA. Anti-sense RNAs or cRNAs are then transcribed from the second strand of the double-stranded cDNAs using an RNA polymerase (see, e.g., U.S. Patent Nos. 5,891,636, 5,716,785; 5,545,522 and 6,132,997; see also, U.S. Patent No. 6,271,002, and U.S. Provisional Patent Application Serial No. 60/253,641, filed on November 28, 2000, by Ziman et al.). Both oligo-dT primers (U.S. Patent Nos. 5,545,522 and 6,132,997) or random primers (U.S. Provisional Patent Application Serial No. 60/253,641, filed on November 28, 2000, by Ziman et al.) that contain an RNA polymerase promoter or complement thereof can be used. In some embodiments the target polynucleotides are short and/or fragmented polynucleotide molecules which are representative of the original nucleic acid population of the sample.

[00157] The target polynucleotides to be analyzed by the methods and compositions of the invention can be detectably labeled. For example, cDNA can be labeled directly, e.g., with nucleotide analogs, or indirectly, e.g., by making a second, labeled cDNA strand using the first strand as a template. Alternatively, the double-stranded cDNA can be transcribed into cRNA and labeled.

[00158] In some embodiments the detectable label is a fluorescent label, e.g., by incorporation of nucleotide analogs. Other labels suitable for use in the present invention include, but are not limited to, biotin, imminobiotin, antigens, cofactors, dinitrophenol, lipoic acid, olefinic compounds, detectable polypeptides, electron rich molecules, enzymes capable of generating a detectable signal by action upon a substrate, and radioactive isotopes. Suitable radioactive isotopes include ³²P, ³⁵S, ¹⁴C, ¹⁵N and ¹²⁵I. Fluorescent molecules suitable for the present invention include, but are not limited to, fluorescein and its derivatives, rhodamine and its derivatives, texas red, 5'carboxy-fluorescein ("FMA"), 2',7'- dimethoxy-4',5'-dichloro-6-carboxy-fluorescein ("JOE"), N,N,N',N'- tetramethyl-6-carboxy- rhodamine ("TAMRA"), 6'carboxy-X-rhodamine ("ROX"), HEX, TET, IRD40, and IRD41. Fluroescent molecules that are suitable for the invention further include: cyamine dyes, including by not limited to Cy3, Cy3.5 and Cy5; BODIPY dyes including but not limited to BODIPY-FL, BODIPY-TR, BODIPY-TMR, BODIPY-630/650, and BODIP Y-650/670; and ALEXA dyes, including but not limited to ALEXA-488, ALEXA-532, ALEXA-546, ALEXA-568, and ALEXA-594; as well as other fluorescent dyes which will be known to those who are skilled in the art. Electron rich indicator molecules suitable for the present invention include, but are not limited to, ferritin, hemocyanin, and colloidal gold. Alternatively, in less some embodiments the target polynucleotides may be labeled by specifically complexing a first group to the polynucleotide. A second group, covalently linked to an indicator molecules and which has an affinity for the first group, can be used to indirectly detect the target polynucleotide. In such an embodiment, compounds suitable for use as a first group include, but are not limited to, biotin and iminobiotin. Compounds suitable for use as a second group include, but are not limited to, avidin and streptavidin. [00159] In a specific embodiment, the target polynucleotides are prepared as follows:

2μg Oligo-dT primers are annealed to 2μg of mRNA isolated from a sample of a patient in a total volume of 15μl, by heating to 70°C for 10 min, and cooled on ice. The mRNA is reverse transcribed by incubating the sample at 42⁰C for 1.5-2 hours in a 100 μl volume containing a final concentration of 5OmM Tris-HCl (pH 8.3), 75mM KCl, 3mM MgCl₂, 25mM DTT, 25mM unlabeled dNTPs, 400 units of Superscript II (200U/μL, Gibco BRL), and 15mM of Cy 3 or Cy5 (Amersham). RNA is then degraded by addition of 15μl of 0.1N NaOH, and incubation at 70°C for 10 min. The reaction mixture is neutralized by addition of 15μl of 0.1N HCl, and the volume is brought to 500μl with TE (1OmM Tris, ImM EDTA), and 20 μg of Cot 1 human DNA (Gibco-BRL) is added.

[00160] The labeled target polynucleotide molecules are purified by centrifugation in a

Centricon-30 micro-concentrator (Amicon). If two different target polynucleotide samples (e.g., two samples derived from a healthy patient vs. patient with a cancer) are being analyzed and compared by hybridization to the same array, each target nucleic acid sample is labeled with a different fluorescent label (e.g., Cy3 and Cy5) and separately concentrated. The separately concentrated target nucleic acid samples (Cy3 and Cy5 labeled) are combined into a fresh centricon, washed with 500μl TE, and concentrated again to a volume of less than 7μl. lμL of lOμg/μl polyA RNA (Sigma, #P9403) and lμl of lOμg/μl tRNA (Gibco-BRL, #15401-011) is added and the volume is adjusted to 9.5μl with distilled water. For final target polynucleotide preparation 2.1μl 20XSSC (1.5M NaCl, 15OmM NaCitrate (pH8.0)) and 0.35μl 10%SDS is added.

HYBRIDIZATION TO MICRO ARRAYS

[00161] In some embodiments, nucleic acid hybridization and wash conditions are chosen so that the polynucleotide molecules to be analyzed by the invention (e.g., "target polynucleotide molecules) specifically bind or specifically hybridize to the complementary polynucleotide sequences of the array, typically to a specific array site, where its complementary DNA is located.

[00162] Arrays containing double-stranded probe DNA situated thereon can be subjected to denaturing conditions to render the DNA single-stranded prior to contacting with the target polynucleotide molecules. Arrays containing single-stranded probe DNA (e.g., synthetic oligodeoxyribonucleic acids) may need to be denatured prior to contacting with the target polynucleotide molecules, e.g., to remove hairpins or dimers which form due to self complementary sequences.

[00163] Optimal hybridization conditions will depend on the length (e.g., oligomer versus polynucleotide greater than 200 bases) and type (e.g., RNA, or DNA) of probe and target nucleic acids. General parameters for specific (i.e., stringent) hybridization conditions for nucleic acids are described in Sambrook et al, (supra), and in Ausubel et al, 1987, Current Protocols in Molecular Biology, Greene Publishing and Wiley-Interscience, New York. When the cDNA microarrays of Schena et al. are used, typical hybridization conditions are hybridization in 5 X SSC plus 0.2% SDS at 65 °C for four hours, followed by washes at 25⁰C in low stringency wash buffer (1 X SSC plus 0.2% SDS), followed by 10 minutes at 25⁰C in higher stringency wash buffer (0.1 X SSC plus 0.2% SDS) (Shena et al., 1996, Proc. Natl. Acad. Sci. U.S.A. 95:10614). Useful hybridization conditions are also provided in, e.g., Tijessen, 1993, Hybridization With Nucleic Acid Probes, Elsevier Science Publishers B. V. and Kricka, 1992, Nonisotopic DNA Probe Techniques, Academic Press, San Diego, CA.

[00164] Representative hybridization conditions for use with the screening and/or signaling chips in accordance with some embodiments of the present invention include hybridization at a temperature at or near the mean melting temperature of the probes (e.g., within 5 ⁰C, more typically within 2 °C) in 1 M NaCl, 50 niM MES buffer (pH 6.5), 0.5% sodium Sarcosine and 30% formamide. [00165] In a specific embodiment, labeled target polynucleotide molecules are denatured by heating for two minutes at 100⁰C, and incubated at 37⁰C for 20-30 min before being placed on a nucleic acid array under a 22mm x 22mm glass cover slip. Hybridization is carried out at 65⁰C for fourteen to eighteen hours in a custom slide chamber with humidity maintained by a small reservoir of 3XSSC. The array is washed by submersion and agitation for between two and five minutes in 2X SSC with 0.1%SDS, followed by IX SSC, and 0.1X SSC. Finally, the array is dried by centrifugation for 2 min in a slide rack in a Beckman GS- 6 tabletop centrifuge in Microplus carriers at 650 RPM for two minutes.

SIGNAL DETECTION AND DATA ANALYSIS

[00166] It will be appreciated that when target sequences, e.g., cDNA or cRNA, complementary to the RNA of a sample is made and hybridized to a microarray under suitable hybridization conditions, the level of hybridization to the site in the array corresponding to an exon of any particular gene will reflect the prevalence in the cell of mRNA or mRNAs containing the exon transcribed from that gene. For example, when detectably labeled (e.g., with a fluorophore) cDNA complementary to the total cellular mRNA is hybridized to a microarray, the site on the array corresponding to an exon of a gene (i.e., capable of specifically binding the product or products of the gene expressing) that is not transcribed or is removed during RNA splicing in the cell will have little or no signal (e.g., fluorescent signal), and an exon of a gene for which the encoded mRNA expressing the exon is prevalent will have a relatively strong signal. The relative abundance of different mRNAs produced from the same gene by alternative splicing is then determined by the signal strength pattern across the whole set of exons monitored for the gene. [00167] In some embodiments, two-color fluorescence is used. The use of a two-color fluorescence labeling and detection scheme to define alterations in gene expression has been described in connection with detection of mRNAs, e.g., in Shena et al., 1995, Science 270:467-470, which is hereby incorporated by reference in its entirety for all purposes. The scheme is equally applicable to labeling and detection of exons. An advantage of using target sequences, e.g., cDNAs or cRNAs, labeled with two different fluorophores is that a direct and internally controlled comparison of the mRNA or exon expression levels corresponding to each arrayed gene in two states can be made, and variations due to minor differences in experimental conditions (e.g., hybridization conditions) will not affect subsequent analyses. [00168] In a specific embodiment, the labeled probes are scanned using a GMS

Scanner 418 and Scananlzyer software (Michael Eisen, Stamford University), followed by GeneSpring software (Silcon Genetics, CA) analysis. In another embodiment, a GMS Scanner 428 and Jaguar software are used followed by GeneSpring software analysis. In some embodiments a normalization routine is used.

5.4.1.2 RT-PCR

[00169] In one embodiment, the level of expression of one or more of the following genes is measured by amplifying RNA from a sample using reverse transcription (RT) in combination with the polymerase chain reaction (PCR): SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATPl 3Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. In accordance with this embodiment, the reverse transcription may be quantitative.

[00170] Total RNA, or mRNA from a sample is used as a template and a primer specific to the transcribed portion of the gene(s) is used to initiate reverse transcription. Methods of reverse transcribing RNA into cDNA are well known and described in Sambrook et al., 1989, supra. Primer design can be accomplished utilizing commercially available software (e.g., Primer Designer 1.0, Scientific Sofware etc.). The product of the reverse transcription is subsequently used as a template for PCR.

[00171] PCR provides a method for rapidly amplifying a particular nucleic acid sequence by using multiple cycles of DNA replication catalyzed by a thermostable, DNA- dependent DNA polymerase to amplify the target sequence of interest. PCR requires the presence of a nucleic acid to be amplified, two single-stranded oligonucleotide primers flanking the sequence to be amplified, a DNA polymerase, deoxyribonucleoside triphosphates, a buffer and salts. The method of PCR is well known in the art. PCR, is performed as described in Mullis and Faloona, 1987, Methods Enzymol, 155: 335, which is incorporated herein by reference.

[00172] PCR is performed using template DNA or cDNA (at least lfg; more usefully,

1-1000 ng) and at least 25 pmol of oligonucleotide primers. A typical reaction mixture includes: 2 μl of DNA, 25 pmol of oligonucleotide primer, 2.5 μl of 10 M PCR buffer 1 (Perkin-Elmer, Foster City, CA), 0.4 μl of 1.25 μM dNTP, 0.15 μl (or 2.5 units) of Taq DNA polymerase (Perkin Elmer, Foster City, CA) and deionized water to a total volume of 25 μl. Mineral oil is overlaid and the PCR is performed using a programmable thermal cycler. The length and temperature of each step of a PCR cycle, as well as the number of cycles, are adjusted according to the stringency requirements in effect. Annealing temperature and timing are determined both by the efficiency with which a primer is expected to anneal to a template and the degree of mismatch that is to be tolerated. The ability to optimize the stringency of primer annealing conditions is well within the knowledge of one of moderate skill in the art. An annealing temperature of between 30⁰C and 72°C is used. Initial denaturation of the template molecules normally occurs at between 92°C and 99°C for 4 minutes, followed by 20-40 cycles consisting of denaturation (94-99°C for 15 seconds to 1 minute), annealing (temperature determined as discussed above; 1-2 minutes), and extension (72⁰C for 1 minute). The final extension step is generally carried out for 4 minutes at 72⁰C, and may be followed by an indefinite (0-24 hour) step at 4°C.

[00173] QRT-PCR, which is quantitative in nature, can also be performed to provide a quantitative measure of gene expression levels. In QRT-PCR reverse transcription and PCR can be performed in two steps, or reverse transcription combined with PCR can be performed concurrently. One of these techniques, for which there are commercially available kits such as Taqman® (Perkin Elmer, Foster City, CA), is performed with a transcript-specific antisense probe. This probe is specific for the PCR product (e.g. a nucleic acid fragment derived from a gene) and is prepared with a quencher and fluorescent reporter probe complexed to the 5' end of the oligonucleotide. Different fluorescent markers are attached to different reporters, allowing for measurement of two products in one reaction. When Taq DNA polymerase is activated, it cleaves off the fluorescent reporters of the probe bound to the template by virtue of its 5'-to-3' exonuclease activity. In the absence of the quenchers, the reporters now fluoresce. The color change in the reporters is proportional to the amount of each specific product and is measured by a fluorometer; therefore, the amount of each color is measured and the PCR product is quantified. The PCR reactions are performed in 96 well plates so that samples derived from many individuals are processed and measured simultaneously. The Taqman® system has the additional advantage of not requiring gel electrophoresis and allows for quantification when used with a standard curve. [00174] A second technique useful for detecting PCR products quantitatively without is to use an intercolating dye such as the commercially available QuantiTect™ SYBR® Green PCR (Qiagen, Valencia California). RT-PCR is performed using SYBR® green as a fluorescent label which is incorporated into the PCR product during the PCR stage and produces a flourescense proportional to the amount of PCR product. [00175] Both Taqman® and QuantiTect™ SYBR® systems can be used subsequent to reverse transcription of RNA. Reverse transcription can either be performed in the same reaction mixture as the PCR step (one-step protocol) or reverse transcription can be performed first prior to amplification utilizing PCR (two-step protocol). [00176] Additionally, other systems to quantitatively measure mRNA expression products are known including Molecular Beacons® which uses a probe having a fluorescent molecule and a quencher molecule, the probe capable of forming a hairpin structure such that when in the hairpin form, the fluorescence molecule is quenched, and when hybridized the flourescense increases giving a quantitative measurement of gene expression. [00177] Additional techniques to quantitatively measure RNA expression include, but are not limited to, polymerase chain reaction, ligase chain reaction, Qbeta replicase (see, e.g., International Application No. PCT/US87/00880), isothermal amplification method (see, e.g., Walker et al. (1992) PNAS 89:382-396), strand displacement amplification (SDA), repair chain reaction, Asymmetric Quantitative PCR (see, e.g., U.S. Publication No. US200330134307A1) and the multiplex microsphere bead assay described in Fuja et al., 2004, Journal of Biotechnology 108:193-205.

[00178] The level of expression of one or more of the following genes can be measured by amplifying RNA from a sample using amplification (NASBA) and 3SR: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib. See, e.g., Kwoh et al (1989) PNAS USA 86:1173; International Publication No. WO 88/10315; and U.S. Patent No. 6,329,179. In NASBA, the nucleic acids may be prepared for amplification using conventional phenol/chloroform extraction, heat denaturation, treatment with lysis buffer and minispin columns for isolation of DNA and RNA or guanidinium chloride extraction of RNA. These amplification techniques involve annealing a primer that has target specific sequences. Following polymerization, DNA/RNA hybrids are digested with RNase H while double stranded DNA molecules are heat denatured again. In either case the single stranded DNA is made fully double stranded by addition of second target specific primer, followed by polymerization. The double-stranded DNA molecules are then multiply transcribed by a polymerase such as T7 or SP6. In an isothermal cyclic reaction, the RNA' s are reverse transcribed into double stranded DNA, and transcribed once with a polymerase such as T7 or SP6. The resulting products, whether truncated or complete, indicate target specific sequences.

[00179] Several techniques may be used to separate amplification products. For example, amplification products may be separated by agarose, agarose-acrylamide or polyacrylamide gel electrophoresis using conventional methods. See Sambrook et al., 1989. Several techniques for detecting PCR products quantitatively without electrophoresis may also be used according to the invention (see for example PCi? Protocols, A Guide to Methods and Applications, Innis et al., Academic Press, Inc. N. Y., (1990)). For example, chromatographic techniques may be employed to effect separation. There are many kinds of chromatography which may be used in the present invention: adsorption, partition, ion- exchange and molecular sieve, HPLC, and many specialized techniques for using them including column, paper, thin-layer and gas chromatography (Freifelder, Physical Biochemistry Applications to Biochemistry and Molecular Biology, 2nd ed., Wm. Freeman and Co., New York, N. Y., 1982).

[00180] Another example of a separation methodology is done by covalently labeling the oligonucleotide primers used in a PCR reaction with various types of small molecule ligands. In one such separation, a different ligand is present on each oligonucleotide. A molecule, perhaps an antibody or avidin if the ligand is biotin, that specifically binds to one of the ligands is used to coat the surface of a plate such as a 96 well ELISA plate. Upon application of the PCR reactions to the surface of such a prepared plate, the PCR products are bound with specificity to the surface. After washing the plate to remove unbound reagents, a solution containing a second molecule that binds to the first ligand is added. This second molecule is linked to some kind of reporter system. The second molecule only binds to the plate if a PCR product has been produced whereby both oligonucleotide primers are incorporated into the final PCR products. The amount of the PCR product is then detected and quantified in a commercial plate reader much as ELISA reactions are detected and quantified. An ELIS A-like system such as the one described here has been developed by the Raggio Italgene company under the C-Track trade name.

[00181] Amplification products must be visualized in order to confirm amplification of the nucleic acid sequences of interest, i.e., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib nucleic acid sequences. One typical visualization method involves staining of a gel with ethidium bromide and visualization under UV light. Alternatively, if the amplification products are integrally labeled with radio- or fluorometrically-labeled nucleotides, the amplification products may then be exposed to x-ray film or visualized under the appropriate stimulating spectra, following separation.

[00182] In one embodiment, visualization is achieved indirectly. Following separation of amplification products, a labeled, nucleic acid probe is brought into contact with the amplified nucleic acid sequence of interest, i.e., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATPl 3Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib nucleic acid sequences. The probe preferably is conjugated to a chromophore but may be radiolabeled. In another embodiment, the probe is conjugated to a binding partner, such as an antibody or biotin, where the other member of the binding pair carries a detectable moiety.

[00183] In another embodiment, detection is by Southern blotting and hybridization with a labeled probe. The techniques involved in Southern blotting are well known to those of skill in the art and may be found in many standard books on molecular protocols. See Sambrook et al., 1989. Briefly, amplification products are separated by gel electrophoresis. The gel is then contacted with a membrane, such as nitrocellulose, permitting transfer of the nucleic acid and non-covalent binding. Subsequently, the membrane is incubated with a chromophore-conjugated probe that is capable of hybridizing with a target amplification product. Detection is by exposure of the membrane to x-ray film or ion-emitting detection devices.

[00184] One example of the foregoing is described in U.S. Pat. No. 5,279,721, incorporated by reference herein, which discloses an apparatus and method for the automated electrophoresis and transfer of nucleic acids. The apparatus permits electrophoresis and blotting without external manipulation of the gel and is ideally suited to carrying out methods according to the present invention.

5.4.1.3 DOT BLOT

[00185] In specific embodiments, nucleic acid (e.g., RNA) dot blot assays be used to detect and quantitate specific mRNAs {i.e., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib mRNAs). DNA/RNA or protein samples are spotted onto a membrane and hybridized with a labeled probe that hybridizes to a specific DNA/RNA or protein molecule.

5.4.1.4 NUCLEASE PROTECTION ASSAYS

[00186] Nuclease protection assays known to those skilled in the art (including both ribonuclease protection assays and Sl nuclease assays) can be used to detect and quantitate specific mRNAs {i.e., SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib mRNAs). In nuclease protection assays, an antisense probe (labeled with, e.g., radiolabeled or nonisotopic) hybridizes in solution to an RNA sample. Following hybridization, single-stranded, unhybridized probe and RNA are degraded by nucleases. An acrylamide gel is used to separate the remaining protected fragments. Typically, solution hybridization is more efficient than membrane-based hybridization, and it can accommodate up to 100 μg of sample RNA, compared with the 20-30 μg maximum of blot hybridizations. [00187] The ribonuclease protection assay, which is the most common type of nuclease protection assay, requires the use of RNA probes. Oligonucleotides and other single-stranded DNA probes can only be used in assays containing Sl nuclease. The single-stranded, antisense probe must typically be completely homologous to target RNA to prevent cleavage of the probe:target hybrid by nuclease.

5.4.1.5 NORTHERN BLOT ASSAY

[00188] A standard Northern blot assay can be used to ascertain an RNA transcript size, identify alternatively spliced RNA transcripts, and the relative amounts of SLC 12 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl₃ FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib RNA (in particular, niRNA) in a sample, in accordance with conventional Northern hybridization techniques known to those persons of ordinary skill in the art. In Northern blots, RNA samples are first separated by size via electrophoresis in an agarose gel under denaturing conditions. The RNA is then transferred to a membrane, crosslinked and hybridized with a labeled probe. Nonisotopic or high specific activity radiolabeled probes can be used including random- primed, nick-translated, or PCR-generated DNA probes, in vitro transcribed RNA probes, and oligonucleotides. Additionally, sequences with only partial homology (e.g., cDNA from a different species or genomic DNA fragments that might contain an exon) may be used as probes. The labeled probe, e.g., a radiolabeled cDNA, either containing the full-length, single stranded DNA or a fragment of that DNA sequence may be at least 20, at least 30, at least 50, or at least 100 consecutive nucleotides in length. The probe can be labeled by any of the many different methods known to those skilled in this art. The labels most commonly employed for these studies are radioactive elements, enzymes, chemicals that fluoresce when exposed to ultraviolet light, and others. A number of fluorescent materials are known and can be utilized as labels. These include, but are not limited to, fluorescein, rhodamine, auramine, Texas Red, AMCA blue and Lucifer Yellow. A particular detecting material is anti-rabbit antibody prepared in goats and conjugated with fluorescein through an isothiocyanate. Proteins can also be labeled with a radioactive element or with an enzyme. The radioactive label can be detected by any of the currently available counting procedures. Non-limiting examples of isotopes include ³H, ¹⁴C, ³²P, ³⁵S, ³⁶Cl, ⁵¹Cr, ⁵⁷Co, ⁵⁸Co, ⁵⁹Fe, ⁹⁰Y, ¹²⁵1, ¹³¹I, and ¹⁸⁶Re. Enzyme labels are likewise useful, and can be detected by any of the presently utilized colorimetric, spectrophotometric, fluorospectrophotometric, amperometric or gasometric techniques. The enzyme is conjugated to the selected particle by reaction with bridging molecules such as carbodiimides, diisocyanates, glutaraldehyde and the like. Any enzymes known to one of skill in the art can be utilized. Examples of such enzymes include, but are not limited to, peroxidase, beta-D-galactosidase, urease, glucose oxidase plus peroxidase and alkaline phosphatase. U.S. Patent Nos. 3,654,090, 3,850,752, and 4,016,043 are referred to by way of example for their disclosure of alternate labeling material and methods.

5.4.2 PROTEIN DETECTION

[00189] Standard techniques can also be utilized for determining the amount of the protein or proteins of interest (that is, SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl. SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein) present in a sample. For example, standard techniques can be employed using, e.g., immunoassays such as, for example, Western blot, immunoprecipitation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), immunocytochemistry, and the like to determine the amount of the protein or proteins of interest present in a sample. A preferred agent for detecting a protein of interest is an antibody capable of binding to a protein of interest, preferably an antibody with a detectable label.

[00190] For such detection methods, protein from the sample to be analyzed can easily be isolated using techniques which are well known to those of skill in the art. Protein isolation methods can, for example, be such as those described in Harlow and Lane (Harlow, E. and Lane, D., 1988, "Antibodies: A Laboratory Manual ", Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York).

[00191] Preferred methods for the detection of the protein or proteins of interest involve their detection via interaction with a protein-specific antibody. For example, antibodies directed a protein of interest can be utilized as described herein. Antibodies can be generated utilizing standard techniques well known to those of skill in the art. See, e.g., Section 5.6.2.2 of this application and Section 5.2 of U.S. Publication No. 20040018200 for a more detailed discussion of such antibody generation techniques, which is incorporated herein by reference. Briefly, such antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or an antibody fragment (e.g., Fab or F(ab')₂) can, for example, be used. Preferably, the antibody is a human or humanized antibody. [00192] For example, antibodies, or fragments of antibodies, specific for a protein of interest can be used to quantitatively or qualitatively detect the presence of the protein. This can be accomplished, for example, by immunofluorescence techniques. Antibodies (or fragments thereof) can, additionally, be employed histologically, as in immunofluorescence or immunoelectron microscopy, for in situ detection of a protein of interest. In situ detection can be accomplished by removing a histological specimen (e.g., a biopsy specimen) from a patient, and applying thereto a labeled antibody thereto that is directed to a SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib protein. The antibody (or fragment) is preferably applied by overlaying the labeled antibody (or fragment) onto a biological sample. Through the use of such a procedure, it is possible to determine not only the presence of the protein of interest, but also its distribution, its presence in lymphocytes within the sample. A wide variety of well-known histological methods (such as staining procedures) can be utilized in order to achieve such in situ detection. [00193] Immunoassays for a protein of interest typically comprise incubating a biological sample of a detectably labeled antibody capable of identifying a protein of interest, and detecting the bound antibody by any of a number of techniques well-known in the art. As discussed in more detail, below, the term "labeled" can refer to direct labeling of the antibody via, e.g., coupling {i.e., physically linking) a detectable substance to the antibody, and can also refer to indirect labeling of the antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody.

[00194] The biological sample can be brought in contact with and immobilized onto a solid phase support or carrier such as nitrocellulose, or other solid support which is capable of immobilizing cells, cell particles or soluble proteins. The support can then be washed with suitable buffers followed by treatment with the detectably labeled fingerprint gene-specific antibody. The solid phase support can then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on solid support can then be detected by conventional means.

[00195] By "solid phase support or carrier " is intended any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. The nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention. The support material can have virtually any possible structural configuration so long as the coupled molecule is capable of binding to an antigen or antibody. Thus, the support configuration can be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface can be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation. [00196] One of the ways in which an SLC12A2, FLJ23375, GRM5, TAS2R1 ,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib protein-specific antibody can be detectably labeled is by linking the same to an enzyme and use in an enzyme immunoassay (EIA) (Voller, A., "The Enzyme Linked Immunosorbent Assay (ELISA)", 1978, Diagnostic Horizons 2:1-7, Microbiological Associates Quarterly Publication, Walkersville, MD); Voller, A. et al, 1978, J. Clin. Pathol. 31:507-520; Butler, J.E., 1981, Meth. Enzymol. 73:482-523; Maggio, E. (ed.), 1980, Enzyme Immunoassay, CRC Press, Boca Raton, FL; Ishikawa, E. et al., (eds.), 1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The enzyme which is bound to the antibody will react with an appropriate substrate, preferably a chromogenic substrate, in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorimetric or by visual means. Enzymes which can be used to detectably label the antibody include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-5- steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. The detection can be accomplished by colorimetric methods which employ a chromogenic substrate for the enzyme. Detection can also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards. [00197] Detection can also be accomplished using any of a variety of other immunoassays. For example, by radioactively labeling the antibodies or antibody fragments, it is possible to detect a protein of interest through the use of a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope {e.g., ¹²⁵1, ¹³¹1, ³⁵S or ³H) can be detected by such means as the use of a gamma counter or a scintillation counter or by autoradiography. [00198] It is also possible to label the antibody with a fluorescent compound. When the fluorescently labeled antibody is exposed to light of the proper wavelength, its presence can then be detected due to fluorescence. Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o -phthaldehyde and fluorescamine.

[00199] The antibody can also be detectably labeled using fluorescence emitting metals such as Eu, or others of the lanthanide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

[00200] The antibody also can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antibody is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.

[00201] Likewise, a bioluminescent compound can be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in, which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Important bioluminescent compounds for purposes of labeling are luciferin, luciferase and aequorin.

[00202] In preferred embodiments, methods for the detection and/or quantification of the protein or proteins of interest (preferably, SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GR1A4, OR4M1, KIAAl 679 and/or UPK-Ib protein) in a sample from a subject involve their detection using isotope- coded affinity tag (ICAT™; Applied Biosystems (ABI), Foster City, CA) quantitative protein profiling by tandem mass spectometry (ICAT-MS/MS). See, for example, Han et al., 2001, Nat. Biotechnol. 19:946-951, which is incorporated by reference herein in its entirety. This technique enables the comparison of protein levels of two biological samples in a relatively quantitative manner. In particular, the method allows for the direct comparison of the relative abundance of cell surface proteins present on cancer cells relative to normal cells. In a first step, plasma membrane proteins are enriched using a glycosylation capture purification method. See, for example, Zhang et al., 2003, Nat. Biotechnol. 21:660-666, which is incorporated by reference herein in its entirety. In a second step, sulfhydryl groups in polypeptide chains with chemically identical but isotopically different reagents. This is followed by proteolysis, isolation of tagged peptides, and mass spectrometric sequence analysis and quantification. The isotope labeling is ¹³C-based, resulting in an exact co- elution of the light and heavy labeled peptide off the reverse phase column and thus facilitating and improving quantification. The biotin portion of the ICAT reagent tag is cleaved with acid after the ICAT™ reagent-labeled peptides are eluted from the aviden cartridge. This reduces the size of the label on the peptide from 442 Da to 227 Da, allowing for analysis of larger peptides (due to limited m/z window). In addition, the MS/MS sequence coverage is improved due to reduced label fragmentation, which improves database searching and confidence in identifications. This technique allows the simultaneous identification of the components of extremely complex protein mixtures together with determination of their relative abundance. The method provided herein is compatible with the analysis of essentially any source of protein, including those harvested from body fluids, cells or tissues.

[00203] In specific embodiments, the generation and analysis of data generated by the

ICAT™ experiments requires analytical software tools with high through-put and a high degree of automation. The LC-MS/MS raw data from each peptide fraction is analyzed by SEQUEST, a program for automated database searching. A second program, XPRESS, uses the SEQUEST data and automatically generates the relative quantification of the proteins and calculates the ratios for the heavy and light ICAT™ labeled peptide pairs. Results from these two programs are uploaded to a database (SBEAMS Proteomics) where the search results from all LC-MS/MS runs can be viewed and interrogated. Data can be filtered by various parameters including the SEQUEST XCorrelation score, or the newly developed peptide probability score (Keller et al., 2002, Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal. Chem. 74, 5383-92, which is incorporated by reference herein in its entirety). The data can also be filtered by whether or not the peptide has tryptic ends (i.e., Arg or Lys prior to the N-terminal amino acid and at the C-terminus of the peptide) or contains missed cleavages (i.e., Arg or Lys internal to the sequence), and the presence of partial amino acid compositions (e.g., cysteine content).

[00204] Various mass spectrometers may be used for the sample analysis, including two fully automated electro-spray ionization (ESI-) ion trap instruments, two ESI- quadrupole time of flight (ESI-QTOF-) MS and a matrix-assisted laser desorption (MALDI)-QTOF-MS. Specific software for the MALDI-QTOF -MS, developed in part in Ruedi Aebersold's group and in part by ABI (Griffin, TJ. et al., 2001, J Am Soc Mass Spectrom 12, 1238-46, which is incorporated by reference herein in its entirety), has the ability to select proteins for identification based on their relative abundance and therefore to focus on differentially expressed proteins. In a specific embodiment, mass spectrometry analysis will is conducted as described by Han et al., 2001, Nat. Biotechnol. 19:946-951.

[00205] In preferred embodiments, the amount of SLC12A2, FLJ23375, GRM5,

TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, . C19orf26, KIAA830, KIAA1244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib protein in a sample from a subject is compared to the amount of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein in a control sample to quantify the relative expression of said proteins in both the subject sample and the control sample using the ICAT-MS/MS technique.

5.5. COMPOUNDS FOR USE IN THE PREVENTION, TREATMENT, MANAGEMENT OR AMELIORATION OF CANCER OR A SYMPTOM THEREOF

5.5.1 METHODS FOR IDENTIFYING COMPOUNDS THAT

MODULATE THE EXPRESSION OR ACTIVITY OF THE GENES AND PROTEINS OF THE INVENTION

[00206] The present invention provides methods of identifying compounds that bind to a gene product or fragment thereof of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1. NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. The present invention also provides methods for identifying compounds that modulate the expression and/or activity of a gene product or fragment thereof of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEMl 6F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. The compounds identified via such methods are useful for the development of one or more animal models to study cancer. Further, the compounds identified via such methods are useful as lead compounds in the development of prophylactic and therapeutic compositions for prevention, treatment, management and/or amelioration of cancer or a symptom thereof. Such methods are particularly useful in that the effort and great expense involved in testing potential prophylactics and therapeutics in vivo is efficiently focused on those compounds identified via the in vitro and ex vivo methods described herein.

[00207] The present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a test compound with a cell expressing a gene product or fragment thereof of one or more of the following genes: (i) SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; and (b) determining the ability of the test compound to bind to the gene product or gene product fragment so that if a compound binds to the gene product or gene product fragment, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. The cell, for example, can be a yeast cell or a cell of mammalian origin. Determining the ability of the test compound to bind to the gene product or gene product fragment can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the gene product or gene product fragment can be determined by detecting the labeled compound in a complex. For example, test compounds

125 35 14 3 can be labeled with I, S, C, or H, either directly or indirectly, and the radioisotope detected by direct counting of radioemmission or by scintillation counting. Alternatively, test compounds can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In a specific embodiment, the assay comprises contacting a cell which expresses a gene product or fragment thereof of a gene described herein with a known compound which binds the gene product or gene product fragment to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with the gene product or gene product fragment, wherein determining the ability of the test compound to interact with the gene product or gene product fragment comprises determining the ability of the test compound to preferentially bind to the gene product or gene product fragment as compared to the known compound.

[00208] The present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a test compound with a gene product or gene product fragment of a gene described herein; and (b) determining the ability of the test compound to bind to the gene product or gene product fragment so that if a compound binds to the gene product or gene product fragment, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. Binding of the test compound to the gene product or gene product fragment can be determined either directly or indirectly. In a specific embodiment, the assay includes contacting a gene product or gene product fragment of a gene described herein with a known compound which binds the gene product or gene product fragment to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with the gene product or gene product fragment, wherein determining the ability of the test compound to interact with the gene product or gene product fragment comprises determining the ability of the test compound to preferentially bind to the gene product or gene product fragment as compared to the known compound. Techniques well known in the art can be used to determine the binding between a test compounds and a gene product or gene product fragment thereof of a gene described herein.

[00209] In more than one embodiment of the above assay methods of the present invention, it may be desirable to immobilize either a gene product or fragment thereof of a gene described herein or a test compound to facilitate separation of complexed from uncomplexed forms of the gene product or gene product fragment, as well as to accommodate automation of the assay. Binding of a test compound to gene product or gene product fragment of a gene described herein can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtitre plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided which adds a domain that allows a protein gene product or gene product fragment to be bound to a matrix. For example, glutathione-S-transferase (GST) fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical; St. Louis, MO) or glutathione derivatized microtitre plates, which are then combined with the test compound and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtitre plate wells are washed to remove any unbound components and complex formation is measured either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of binding of a gene product or gene product fragment can be determined using standard techniques.

[00210] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, a gene product or gene product fragment of a gene described herein can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated polypeptide of the invention or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well known in the art (e.g., biotinylation kit, Pierce Chemicals; Rockford, IL), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein can be derivatized to the wells of the plate, and protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEMl 6F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein, or a fragment thereof, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the polypeptide of the invention or target molecule. [00211] The interaction or binding of an SLC12A2, FLJ23375, GRM5, TAS2R1,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP 13Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib protein, or a fragment thereof, to a test compound can also be determined using such proteins or protein fragments as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Bio/Techniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and International Publication No. WO 94/10300).

[00212] The present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a cell expressing a gene product(s) or a fragment thereof of a gene described herein with a test compound; (b) determining the amount of the gene product(s) or gene product fragment(s) present in (a); and (c) comparing the amount(s) in (a) to that/those present in a corresponding control cell that has not been contacted with the test compound, so that if the amount of the gene product(s) or gene product fragment(s) is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In a specific embodiment, the expression level(s) is altered by 5%, 10%, 15%, 25%, 50%, or 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at lease 4 fold, at least 5 fold, at least 10 fold or at least 25 fold relative to the expression level in the control sample as determined by utilizing an assay described herein (e.g., RNA dot-blot, RT-PCR or ICAT-MS/MS) or an assay well known to one of skill in the art. In certain embodiments, such a method comprises determining the amount of a gene product or fragment thereof of at least two, at least three, or all of the genes present in the cell and comparing the amounts to those present in the control. [00213] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell (e.g., a colon, lung, ovary, prostate or pancreas cell) expressing a gene product or fragment thereof of a gene described herein with a test compound; (b) determining the amount of the gene product or gene product fragment present in (a); and (c) comparing the amount in (a) to that present in a corresponding control cell that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the expression of a gene product or fragment thereof of at least one, at least two or all of the genes described herein, present in the cell (e.g., a colon, lung, ovary, prostate or pancreas cell) and comparing the amounts to those present in the control. In specific embodiments, the expression level(s) is decreased by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT-PCR) or an assay well-known to one of skill in the art.

[00214] The present invention also provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell-free extract with a nucleic acid sequence comprising a nucleotide sequence encoding a gene product or fragment thereof of a gene described herein and test compound; (b) determining the amount of at least one of the gene product or gene fragment present in (a); and (c) comparing the amount(s) in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In specific embodiments, the expression level(s) is altered by 5%, 10%, 15%, 25%, 30%, 40%, 50%, or 75%, or by at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold relative to the expression level in the control as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT-PCR) or an assay well known to one of skill in the art. In alternate embodiments, such a method comprises determining the amount of a gene product or fragment thereof of at least two, at least three, or all of the genes described herein present in the extract and comparing the amounts to those present in the control. [00215] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a cell-free extract (e.g., a colon, lung, ovary, prostate or pancreas cell extract) with a nucleic acid sequence comprising a nucleotide sequence encoding a gene product or fragment thereof of a gene product described herein and a test compound; (b) determining the amount of the gene product or gene product fragment present in (a); and (c) comparing the amount in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the expression of a gene product or fragment thereof of at least one, at least two or all of the of the genes described herein, present in the extract and comparing the amounts to those present in the control. In specific embodiments, the expression level(s) is decreased by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold as determined by utilizing an assay described herein (e.g., RNA dot-blot or RT-PCR) or an assay well-known to one of skill in the art.

[00216] The cells utilized in the cell-based assays described above can be engineered to express the gene of interest utilizing techniques known in the art. See, e.g., Section III entitled "Recombinant Expression Vectors and Host Cells" of U.S. Patent No. 6,245,527, which is incorporated herein by reference. Alternatively, cells that endogenously express the gene of interest can be used. For example, prostate cells, ovary cells, lung cells, colon cells or bladder cells may be used.

[00217] In certain embodiments, the amount of mRNA is determined; in other embodiments, the amount of protein is determined, while in still other embodiments, the amount of mRNA and protein is determined. Standard methods for determining the amount of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib mRNA or protein can be utilized. Such methods are described in detail, supra, in Sections 5.4.1 and 5.4.2. [00218] Reporter gene-based assays may also be conducted to identify a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof. In a specific embodiment, the present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a testF compound with a cell expressing a reporter gene construct comprising a reporter gene operably linked to a regulatory element (e.g., a promoter enhancer element) of one of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; (b) measuring the expression of said reporter gene; and (c) comparing the amount in (a) to that present in a corresponding control cell that has not been contacted with the test compound, so that if the amount of expressed reporter gene is altered relative to the amount in the control cell, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, the cell may be engineered to express the reporter gene. In another embodiment, the present invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a test compound with a cell-free extract and a reporter gene construct comprising a reporter gene operably linked to a regulatory element of one of the following genes: SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; (b) measuring the expression of said reporter gene; and (c) comparing the amount in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the amount of expressed reporter gene is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified.

[00219] Any reporter gene well-known to one of skill in the art may be used in reporter gene constructs used in accordance with the methods of the invention. Reporter genes refer to a nucleotide sequence encoding a protein that is readily detectable either by its presence (by, e.g., RT-PCR, Northern blot, Western Blot, ELISA, etc.) or activity. Non-limiting examples of reporter genes are listed in Table 2, infra. Reporter genes may be obtained and the nucleotide sequence of the elements determined by any method well-known to one of skill in the art. The nucleotide sequence of a reporter gene can be obtained, e.g., from the literature or a database such as GenBank. Alternatively, a polynucleotide encoding a reporter gene may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular reporter gene is not available, but the sequence of the reporter gene is known, a nucleic acid encoding the reporter gene may be chemically synthesized or obtained from a suitable source {e.g., a cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the reporter gene) by PCR amplification. Once the nucleotide sequence of a reporter gene is determined, the nucleotide sequence of the reporter gene may be manipulated using methods well-known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY, which are both incorporated by reference herein in their entireties), to generate reporter genes having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.

Table 2: Reporter Genes and the Properties of the Reporter Gene Products

Reporter Gene Protein Activity & Measurement

CAT (chloramphenicol acetyltransferase) ransfers radioactive acetyl groups to chloramphenicol or detection by thin layer chromatography and autoradiography

GAL (beta-galactosidase) Hydrolyzes colorless galactosides to yield colored products. GUS (beta-glucuronidase) Hydrolyzes colorless glucuronides to yield colored products.

LUC (luciferase) Oxidizes luciferin, emitting photons

GFP (green fluorescent protein) Fluorescent protein without substrate

SEAP (secreted alkaline phosphatase) Luminescence reaction with suitable substrates or with substrates that generate chromophores

HRP (horseradish peroxidase) In the presence of hydrogen oxide, oxidation of 3,3',5,5'-tetramethylbenzidine to form a colored complex AP (alkaline phosphatase) Luminescence reaction with suitable substrates or with substrates that generate chromophores

[00220] In accordance with the invention, cells that naturally or normally express one or more, or a combination of the following genes can be used in the methods described herein: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681. C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. Alternatively, cells can be engineered to express one or more, or a combination of the following genes or a reporter gene using techniques well-known in the art and used in the methods described herein: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. Examples of such techniques include, but are not to, calcium phosphate precipitation (see, e.g., Graham & Van der Eb, 1978, Virol. 52:546), dextran-mediated transfection, calcium phosphate mediated transfection, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the nucleic acid in liposomes, and direct microinjection of the nucleic acid into nuclei.

[00221] In a specific embodiment, the cells used in the methods described herein are colon cells, lung cells, ovary cells, prostate cells and pancreas cells. In another embodiment, the cells used in the methods described herein are immortalized cell lines derived from a source, e.g., a tissue.

[00222] Any cell-free extract that permits the translation, and optionally but preferably, the transcription, of a nucleic acid can be used in accordance with the methods described herein. The cell-free extract may be isolated from cells of any species origin. For example, the cell-free translation extract may be isolated from human cells, cultured mouse cells, cultured rat cells, Chinese hamster ovary (CHO) cells, Xenopus oocytes, rabbit reticulocytes, wheat germ, or rye embryo (see, e.g., Krieg & Melton, 1984, Nature 308:203 and Dignam et al., 1990 Methods Enzymol. 182:194-203). Alternatively, the cell-free translation extract, e.g., rabbit reticulocyte lysates and wheat germ extract, can be purchased from, e.g., Promega, (Madison, WI). In a preferred embodiment, the cell-free extract is an extract isolated from human cells. In a specific embodiment, the human cells are LNCaP cells. [00223] In addition to the ability to modulate the expression levels of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP 13Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib as described herein, it may be desirable, at least in certain instances, that compounds modulate the activity of a gene product of such gene(s). Thus, the present invention provides methods of identifying compounds to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, comprising methods for identifying compounds that modulate the activity of a gene product of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. Such methods can comprise: (a) contacting a test compound with a cell expressing a gene product of one or more of the following genes: expressing SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; (b) determining the activity of the gene product; and (c) comparing the activity level or levels to that/those in a corresponding control cell that has not been contacted with the test compound, so that if the level activity in (a) is altered relative to the level of activity in the control sample, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In specific embodiments, the activity level(s) is altered by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold or at least 25 fold relative to the activity level in the control sample. In alternate embodiments, such a method comprises determining the activity level of a gene product of at least two, at least three, or all of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib present in the cell and comparing the activity levels to those present in the control. [00224] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a test compound with a cell (e.g., a colon cell, lung cell, ovary cell, prostate cell or pancreas cell) expressing a gene product of any one of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib; (b) determining the activity of the gene product; and (c) comparing the activity level to that present in a corresponding control cell that has not been contacted with the test compound, so that if the activity level of the gene product is decreased (by, e.g., 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or 1 fold, 1.5 fold, 2 fold, 4 fold, 5 fold, 10 fold, 15 fold or 25 fold) relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the activity level of a gene product of at least one, at least two or all of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib, present in the cell and comparing the activity levels to those present in the control.

[00225] The present invention provides methods of identifying compounds to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, comprising: (a) contacting a test compound with cell-free extract with a nucleic acid comprising a nucleotide sequence encoding any one of the following genes: SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib; (b) determining the activity of the gene product; and (c) comparing the activity level to that in a corresponding control that has not been contacted with the test compound, so that if the level of activity of the gene product in (a) is altered relative to the level of activity in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In alternate embodiments, such a method comprises determining the activity level of a gene product of at least two, at least three, or all of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1 , NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib present in the extract and comparing the activity levels to those present in the control. In accordance with these embodiments, the activity is preferably altered by 5%, 10%, 15%, 25%, 30%, 40%, 50% or 75%, or at least 1 fold, at least 1.5 fold, at least 2 fold, at least 4 fold, at least 5 fold, at least 10 fold, at least 15 fold or at least 25 fold relative to the control as determined by utilizing an assay described herein or well known to one of skill in the art.

[00226] In a specific embodiment, the invention provides a method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a test compound with a cell-free extract (e.g., a prostate, ovary, lung, colon or bladder extract) and a nucleic acid sequence comprising a nucleotide sequence of one of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orO, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJl 4681, C20orf22, FLJl 4281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib; (b) determining the activity level of the gene product; and (c) comparing the activity level in (a) to that present in a corresponding control that has not been contacted with the test compound, so that if the activity level of the gene product is decreased relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified. In accordance with this embodiment, such a method may comprise determining the activity level of a gene product of at least one, at least two or all of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib, present in the extract and comparing the activity levels to those present in the control.

[00227] Standard techniques can be utilized to determine the level of activity of a gene product of a gene described herein. For example, the signal transduction, phosphorylation and proliferation induced by a gene product of a gene described herein can be determined using, for example, immunoassays, electromobility shift assays (EMSA) and tryplan blue counts.

5.5.2 BIOLOGICAL ACTIVITY OF COMPOUNDS

[00228] Upon identification of compounds to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof (for convenience referred to herein as a "lead" compound), the compounds can be further investigated. For example, the compounds identified via the present methods can be further tested in vivo in accepted animal models of cancer. Further, the compounds identified via the methods can be analyzed with respect to their specificity. Techniques for such additional compound investigation are well known to one of skill in the art.

[00229] In one embodiment, the effect of a lead compound can be assayed by measuring the cell growth or viability of the target cell. Such assays can be carried out with representative cells of cell types involved in cancer (e.g., colon, lung, ovarian, prostate and pancreatic cancer). Alternatively, instead of culturing cells from a patient, a lead compound may be screened using cells of a cell line, e.g., a tumor cell line. A lower level of proliferation or survival of the contacted cells indicates that the lead compound has utility to prevent, treat, manage or ameliorate cancer in a patient.

[00230] Many assays well-known in the art can be used to assess the survival and/or growth of a patient cell or cell line following exposure to a lead compound; for example, cell proliferation can be assayed by measuring Bromodeoxyuridine (BrdU) incorporation (see, e.g., Hoshino et al., 1986, Int. J. Cancer 38, 369; Campana et al, 1988, J. Immunol. Meth.

107:79) or (³H)-thymidine incorporation (see, e.g., Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995, J. Biol. Chem. 270:18367-73), by direct cell count, by detecting changes in transcription, translation or activity of known genes such as proto-oncogenes {e.g., fas, myc) or cell cycle markers (Rb, cdc2, cyclin A, Dl, D2, D3, E, etc). The levels of such protein and mRNA and activity can be determined by any method well known in the art. For example, protein can be quantitated by known immunodiagnostic methods such as Western blotting or immunoprecipitation using commercially available antibodies. mRNA can be quantitated using methods that are well known and routine in the art, for example, using RNA dot blot analysis, Northern analysis, RNase protection, the polymerase chain reaction in connection with the reverse transcription and dot blot analysis. Cell viability can be assessed by using trypan-blue staining or other cell death or viability markers known in the art. In a specific embodiment, the level of cellular ATP is measured to determined cell viability. Differentiation can be assessed, for example, visually based on changes in morphology. [00231] The protocols and compositions of the invention are preferably tested in vitro, and then in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays which can be used to determine whether administration of a specific therapeutic protocol is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a protocol, and the effect of such protocol upon the tissue sample is observed. A lower level of proliferation or survival of the contacted cells indicates that the lead compound has utility to prevent, treat, manage or ameliorate cancer in a patient.

[00232] Compounds for use in therapy can be tested in suitable animal model systems prior to testing in humans, including but not limited to in rats, mice, chicken, cows, monkeys, rabbits, hamsters, etc. The anti-cancer activity of the therapies used in accordance with the present invention also can be determined by using various experimental animal models for the study of cancer such as the SCID mouse model, a transgenic mice mouse model, nude mice with human xenografts, or any animal model (including hamsters, rabbits, etc.) known in the art and described in Relevance of Tumor Models for Anticancer Drug Development (1999, eds. Fiebig and Burger); Contributions to Oncology (1999, Karger); The Nude Mouse in Oncology Research (1991, eds. Boven and Winograd); and Anticancer Drug Development Guide (1997 ed. Teicher), herein incorporated by reference in their entireties. The compounds can then be used in the appropriate clinical trials. [00233] Further, any assays known to those skilled in the art can be used to evaluate the prophylactic and/or therapeutic utility of the combinatorial therapies disclosed herein for treatment, prevention, management or amerlioration of cancer or a symptom therof. [00234] Toxicity and efficacy of the prophylactic or therapeutic agents (e.g., lead compounds) of the present invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Prophylactic and/or therapeutic agents (e.g., lead compounds) that exhibit large therapeutic indices are preferred. While prophylactic and/or therapeutic agents (e.g., lead compounds) that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[00235] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage of the prophylactic and/or therapeutic agents for use in humans. The dosage of such agents lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agent used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

5.5.2.1 DESIGN OF COGENERS OR ANALOGS

[00236] The compounds which display the desired biological activity can be used as lead compounds for the development or design of congeners or analogs having useful pharmacological activity. For example, once a lead compound is identified, molecular modeling techniques can be used to design variants of the compound that can be more effective. Examples of molecular modeling systems are the CHARM and QUANTA programs (Polygen Corporation, Waltham, MA). CHARM performs the energy minimization and molecular dynamics functions. QUANTA performs the construction, graphic modelling and analysis of molecular structure. QUANTA allows interactive construction, modification, visualization, and analysis of the behavior of molecules with each other.

[00237] A number of articles review computer modeling of drugs interactive with specific proteins, such as Rotivinen et al., 1988, Acta Pharmaceutical Fennica 97:159-166; Ripka, 1998, New Scientist 54-57; McKinaly & Rossmann, 1989, Annu. Rev. Pharmacol. Toxiciol. 29:111-122; Perry & Davies, OSAR: Quantitative Structure-Activity Relationships in Drug Design pp. 189-193 (Alan R. Liss, Inc. 1989); Lewis & Dean, 1989, Proc. R. Soc. Lond. 236:125-140 and 141-162; Askew et al., 1989, J. Am. Chem. Soc. 111:1082-1090. Other computer programs that screen and graphically depict chemicals are available from companies such as BioDesign, Inc. (Pasadena, California), Allelix, Inc. (Mississauga, Ontario, Canada), and Hypercube, Inc. (Cambridge, Ontario). Although these are primarily designed for application to drugs specific to particular proteins, they can be adapted to design of drugs specific to any identified region. The analogs and congeners can be tested for binding to the proteins of interest using the above-described screens for biologic activity. Alternatively, lead compounds with little or no biologic activity, as ascertained in the screen, can also be used to design analogs and congeners of the compound that have biologic activity.

5.5.3 COMPOUNDS

[00238] Compounds that can be tested and identified methods described herein can include, but are not limited to, compounds obtained from any commercial source, including Aldrich (1001 West St. Paul Ave., Milwaukee, WI 53233), Sigma Chemical (P.O. Box 14508, St. Louis, MO 63178), Fluka Cliemie AG (Industriestrasse 25, CH-9471 Buchs, Switzerland (Fluka Chemical Corp. 980 South 2nd Street, Ronkonkoma, NY 11779)), Eastman Chemical Company, Fine Chemicals (P.O. Box 431, Kingsport, TN 37662), Boehringer Mannheim GmbH (Sandhofer Strasse 116, D-68298 Mannheim), Takasago (4 Volvo Drive, Rockleigh, NJ 07647), SST Corporation (635 Brighton Road, Clifton, NJ 07012), Ferro (111 West Irene Road, Zachary, LA 70791), Riedel-deHaen Aktiengesellschaft (P.O. Box D-30918, Seelze, Germany), PPG Industries Inc., Fine Chemicals (One PPG Place, 34th Floor, Pittsburgh, PA 15272). Further any kind of natural products may be screened using the methods of the invention, including microbial, fungal, plant or animal extracts. [00239] In a specific embodiment, a compound of the invention comprises an antibody, preferably a monoclonal antibody specific for a protein encoded by a gene described herein (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib). In another specific embodiment, a compound of the invention comprises an antibody with a variant Fc region with enhanced activity (see U.S. Appn. Nos. 10/902,588, filed July 28, 2004; 10/754,922, filed January 9, 2004; 60/514,549, filed October 23, 2003; 60/456,041, filed March 19, 2003; and 60/439,498, filed January 9, 2003, all entitled "Identification and Engineering of Antibodies With Variant Fc Regions and Methods of Using Same," and each of which is incorporated by reference herein in its entirety). In accordance with this embodiment, the modified Fc region binds to activating receptors on immune effector cells (e.g., macrophages, natural killer cells, B-cells and/or neutrophils) with greater selectivity and affinity to enhance effector cell response. In specific embodiments, the receptors on the effector cells are CDl 6 A and/or CD32A. In other specific embodiments, the receptors on the effector cells are not CD16A or CD32A.

[00240] Furthermore, diversity libraries of test compounds, including small molecule test compounds, may be utilized. Libraries screened using the methods of the present invention can comprise a variety of types of compounds. Examples of libraries that can be screened in accordance with the methods of the invention include, but are not limited to, peptoids; random biooligomers; diversomers such as hydantoins, benzodiazepines and dipeptides; vinylogous polypeptides; nonpeptidal peptidomimetics; oligocarbamates; peptidyl phosphonates; peptide nucleic acid libraries; antibody libraries; carbohydrate libraries; and small molecule libraries (preferably, small organic molecule libraries). In some embodiments, the compounds in the libraries screened are nucleic acid or peptide molecules. In a non-limiting example, peptide molecules can exist in a phage display library. In other embodiments, the types of compounds include, but are not limited to, peptide analogs including peptides comprising non-naturally occurring amino acids, e.g., D-amino acids, phosphorous analogs of amino acids, such as α-amino phosphoric acids and α-amino phosphoric acids, or amino acids having non-peptide linkages, nucleic acid analogs such as phosphorothioates and PNAs, hormones, antigens, synthetic or naturally occurring drugs, opiates, dopamine, serotonin, catecholamines, thrombin, acetylcholine, prostaglandins, organic molecules, pheromones, adenosine, sucrose, glucose, lactose and galactose. Libraries of polypeptides or proteins can also be used in the assays of the invention. [00241] In a specific embodiment, the combinatorial libraries are small organic molecule libraries including, but not limited to, benzodiazepines, isoprenoids, thiazolidinones, metathiazanones, pyrrolidines, morpholino compounds, and benzodiazepines. In another embodiment, the combinatorial libraries comprise peptoids; random bio-oligomers; benzodiazepines; diversomers such as hydantoins, benzodiazepines and dipeptides; vinylogous polypeptides; nonpeptidal peptidomimetics; oligocarbamates; peptidyl phosphonates; peptide nucleic acid libraries; antibody libraries; or carbohydrate libraries. Combinatorial libraries are themselves commercially available. For example, libraries may be commercially obtained from, e.g., Specs and BioSpecs B. V. (Rijswijk, The Netherlands), Chembridge Corporation (San Diego, CA), Contract Service Company (Dolgoprudny, Moscow Region, Russia), Comgenex USA Inc. (Princeton, NJ), Maybridge Chemicals Ltd. (Cornwall PL34 OHW, United Kingdom), Asinex (Moscow, Russia), ComGenex (Princeton, New Jersey), Ru, Tripos, Inc. (St. Louis, Missouri), ChemStar, Ltd (Moscow, Russia), 3D Pharmaceuticals (Exton, Pennsylvania), and Martek Biosciences (Columbia, Maryland).

[00242] In a preferred embodiment, the library is preselected so that the compounds of the library are more amenable for cellular uptake. For example, compounds are selected based on specific parameters such as, but not limited to, size, lipophilicity, hydrophilicity, and hydrogen bonding, which enhance the likelihood of compounds getting into the cells. In another embodiment, the compounds are analyzed by three-dimensional or four-dimensional computer computation programs.

[00243] The combinatorial compound library for use in accordance with the methods of the present invention may be synthesized. There is a great interest in synthetic methods directed toward the creation of large collections of small organic compounds, or libraries, which could be screened for pharmacological, biological or other activity. The synthetic methods applied to create vast combinatorial libraries are performed in solution or in the solid phase, i.e., on a solid support. Solid-phase synthesis makes it easier to conduct multi-step reactions and to drive reactions to completion with high yields because excess reagents can be easily added and washed away after each reaction step. Solid-phase combinatorial synthesis also tends to improve isolation, purification and screening. However, the more traditional solution phase chemistry supports a wider variety of organic reactions than solid-phase chemistry.

[00244] Combinatorial compound libraries of the present invention may be synthesized using the apparatus described in U.S. Patent No. 6,190,619 to Kilcoin et al., which is hereby incorporated by reference in its entirety. U.S. Patent No. 6,190,619 discloses a synthesis apparatus capable of holding a plurality of reaction vessels for parallel synthesis of multiple discrete compounds or for combinatorial libraries of compounds.

[00245] In one embodiment, the combinatorial compound library can be synthesized in solution. The method disclosed in U.S. Patent No. 6,194,612 to Boger et al., which is hereby incorporated by reference in its entirety, features compounds useful as templates for solution phase synthesis of combinatorial libraries. The template is designed to permit reaction products to be easily purified from unreacted reactants using liquid/liquid or solid/liquid extractions. The compounds produced by combinatorial synthesis using the template will preferably be small organic molecules. Some compounds in the library may mimic the effects of non-peptides or peptides. In contrast to solid phase synthesize of combinatorial compound libraries, liquid phase synthesis does not require the use of specialized protocols for monitoring the individual steps of a multistep solid phase synthesis (Egner et al., 1995, J.Org. Chem. 60:2652; Anderson et al., 1995, J. Org. Chem. 60:2650; Fitch et al., 1994, J. Org. Chem. 59:7955; Look et al., 1994, J. Org. Chem. 49:7588; Metzger et al., 1993, Angew. Chem., Int. Ed. Engl. 32:894; Youngquist et al., 1994, Rapid Commun. Mass Spect. 8:77; Chu et al., 1995, J. Am. Chem. Soc. 117:5419; Brummel et al., 1994, Science 264:399; and Stevanovic et al., 1993, Bioorg. Med. Chem. Lett. 3:431).

[00246] Combinatorial compound libraries useful for the methods of the present invention can be synthesized on solid supports. In one embodiment, a split synthesis method, a protocol of separating and mixing solid supports during the synthesis, is used to synthesize a library of compounds on solid supports (see e.g. , Lam et al., 1997, Chem. Rev. 97:41-448; Ohlmeyer et al., 1993, Proc. Natl. Acad. Sci. USA 90:10922-10926 and references cited therein). Each solid support in the final library has substantially one type of compound attached to its surface. Other methods for synthesizing combinatorial libraries on solid supports, wherein one product is attached to each support, will be known to those of skill in the art (see, e.g., Nefzi et al, 1997, Chem. Rev. 97:449-472).

[00247] As used herein, the term "solid support" is not limited to a specific type of solid support. Rather a large number of supports are available and are known to one skilled in the art. Solid supports include silica gels, resins, derivatized plastic films, glass beads, cotton, plastic beads, polystyrene beads, alumina gels, and polysaccharides. A suitable solid support may be selected on the basis of desired end use and suitability for various synthetic protocols. For example, for peptide synthesis, a solid support can be a resin such as p- methylbenzhydrylamine (pMBHA) resin (Peptides International, Louisville, KY), polystyrenes (e.g., PAM-resin obtained from Bachem Inc., Peninsula Laboratories, etc.), including chloromethylpolystyrene, hydroxymethylpolystyrene and aminomethylpolystyrene, poly (dimethylacrylarnide)-grafted styrene co-divinyl-benzene (e.g., POLYHIPE resin, obtained from Aminotech, Canada), polyamide resin (obtained from Peninsula Laboratories), polystyrene resin grafted with polyethylene glycol (e.g., TENTAGEL or ARGOGEL, Bayer, Tubingen, Germany) polydimethylacrylamide resin (obtained from Milligen/Biosearch, California), or Sepharose (Pharmacia, Sweden).

[00248] In some embodiments of the present invention, compounds can be attached to solid supports via linkers. Linkers can be integral and part of the solid support, or they may be nonintegral that are either synthesized on the solid support or attached thereto after synthesis. Linkers are useful not only for providing points of compound attachment to the solid support, but also for allowing different groups of molecules to be cleaved from the solid support under different conditions, depending on the nature of the linker. For example, linkers can be, inter alia, electrophilically cleaved, nucleophilically cleaved, photocleavable, enzymatically cleaved, cleaved by metals, cleaved under reductive conditions or cleaved under oxidative conditions. In a preferred embodiment, the compounds are cleaved from the solid support prior to high throughput screening of the compounds. [00249] If the library comprises arrays or microarrays of compounds, wherein each compound has an address or identifier, the compound can be deconvoluted, e.g., by cross- referencing the positive sample to the original compound list that was applied to the individual test assays.

[00250] If the library is a peptide or nucleic acid library, the sequence of the compound can be determined by direct sequencing of the peptide or nucleic acid. Such methods are well known to one of skill in the art. [00251] A number of physico-chemical techniques can be used for the de novo characterization of compounds. Examples of such techniques include, but are not limited to, mass spectrometry, NMR spectroscopy, X-ray crytallography and vibrational spectroscopy.

5.6. THERAPEUTIC AND PROPHYLACTIC METHODS

[00252] The present invention provides methods of preventing, treating, managing or ameliorating cancer or a symptom thereof, said methods comprising administering to a subject in need thereof one or more compounds identified in accordance with the methods of the invention. The invention also provides methods of preventing, treating, managing or ameliorating cancer or a symptom thereof, said methods comprising administering to a subject in need thereof one or more of the compounds identified utilizing the methods described herein, and one or more other therapies (e.g., prophylactic or therapeutic agents and/or surgery). In a specific embodiment, such therapies are currently being used, have been used or are known to be useful in the prevention, treatment, management or amelioration of cancer or a symptom thereof (including, but not limited to the prophylactic or therapeutic agents listed herein). In certain embodiments, the subject has benign, malignant or metastatic cancer or malignant cancer. In other embodiments, the cancer has metastasized to sites distal to the primary cancer.

[00253] The methods of the invention further comprise the administration of an effective amount of one or more therapies (e.g., prophylactic or therapeutic agents) that modulate the expression and/or activity of one or more cancer targets disclosed herein (e.g., one or more targets disclosed in Table 1, supra) for the prevention, treatment, management and amelioration of cancer. In a specific embodiment, such therapies are currently being used, have been used or are known to be useful in the prevention, treatment, management or amelioration of cancer or a symptom thereof (including, but not limited to the prophylactic or therapeutic agents listed herein).

[00254] In one embodiment, the invention provides a method of preventing, treating, managing or ameliorating cancer or a symptom thereof, said method comprising administering to a subject in need thereof a dose of a prophylactically or therapeutically effective amount of one or more compounds identified in accordance with the methods of the invention, hi another embodiment, a compound identified in accordance with the methods of the invention is not administered to prevent, treat, or ameliorate cancer or a symptom thereof, if such compound has been used previously to prevent, treat, manage or ameliorate cancer or a symptom thereof. [00255] In a specific embodiment, the invention provides a method of preventing, treating, managing or ameliorating cancer or a symptom thereof, said method comprising administering to a subject in need thereof a dose of a prophylactically or therapeutically effective amount of an antibody identified in accordance with the methods of the invention. In accordance with this embodiment, the antibody is specific for a gene product or gene product fragment encoded by a gene described herein (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib).

[00256] In another specific embodiment, the antibody to be used in the methods of the invention comprises a variant Fc region with enhanced activity (see U.S. Appn. Nos. 10/902,588, filed July 28, 2004; 10/754,922, filed January 9, 2004; 60/514,549, filed October 23, 2003; 60/456,041, filed March 19, 2003; and 60/439,498, filed January 9, 2003, all entitled "Identification and Engineering of Antibodies With Variant Fc Regions and Methods of Using Same," and each of which is incorporated by reference herein in its entirety). In accordance with this embodiment, the modified Fc region binds to activating receptors on immune effector cells (e.g., macrophages, natural killer cells, B-cells and/or neutrophils) with greater selectivity and affinity to enhance effector cell response. In specific embodiments, the receptors on the effector cells are CD16A and/or CD32A. In other specific embodiments, the receptors on the effector cells are not CD16A or CD32A.

[00257] The invention also provides methods of preventing, treating, managing or ameliorating cancer or a symptom thereof, said methods comprising administering to a subject in need thereof one or more of the compounds identified utilizing the screening methods described herein, and one or more other therapies (e.g., prophylactic or therapeutic agents and surgery). In a specific embodiment, such therapies are currently being used, have been used or are known to be useful in the prevention, treatment, management or amelioration of cancer or a symptom thereof (including, but not limited to the prophylactic or therapeutic agents listed in Section 5.6.2 hereinbelow). The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the invention can be administered sequentially or concurrently. In a specific embodiment, the combination therapies of the invention comprise a compound identified in accordance with the invention and at least one other therapy that has the same mechanism of action as said compound. In another specific embodiment, the combination therapies of the invention comprise a compound identified in accordance with the methods of the invention and at least one other therapy (e.g., prophylactic or therapeutic agent) which has a different mechanism of action than said compound. The combination therapies of the present invention improve the prophylactic or therapeutic effect of a compound of the invention by functioning together with the compound to have an additive or synergistic effect. The combination therapies of the present invention reduce the side effects associated with the therapies (e.g., prophylactic or therapeutic agents). In specific embodiments, a therapy to be co-administered with the compounds identified by the methods of the present invention include, but are not limited to, chemotherapy, biological therapy, immunotherapy, radiation therapy, and surgery. Cancer therapies and their dosages, routes of administration and recommended usage are known in the art and have been described in such literature as the Physician ^!s Desk Reference (59^m ed., 2005). [00258] In another specific embodiment, the invention provides methods of preventing, treating, managing or ameliorating cancer or a symptom thereof, said methods comprising co-administering to a subject in need thereof one or more compounds identified in accordance with the methods of the invention with an antibody specific to CD32B. In a preferred embodiment, the anti-CD32B antibody is humanized. In another preferred embodiment, the anti-CD32B antibody is non-humanized. In accordance with these embodiments, CD32B is overexpressed in cancer cells (e.g., cancer cells of the colon, lung, ovary, prostate and/or pancreas) relative to normal cells. Also in accordance with these embodiments, the anti-CD32B antibodies block Fc engagement of CD32B and improve the efficacy of other prophylactic and/or therapeutic agents when co-administered. See, e.g., U.S. Appn. Ser. No. 10/524,134, filed February 11, 2005, entitled "Anti-FcRIIB Monoclonal Antibodies and Their Use in Enhancing Immune Response"; U.S. Appn. Ser. No. 10/643,857, filed August 14, 2003, entitled "FcγRIB-Specific Antibodies and Methods of Use Thereof; U.S. Appn. Ser. No. 11/108,135, filed April 15, 2005, entitled "Humanized FcγRIIB-Specific Antibodies and Methods of Use Thereof; U.S. Appn. Ser. No. 11/126,978, filed May 10, 2005, entitled "Humanized FcγRIIB-Specific Antibodies and Methods of Use Thereof; U.S. Prov. Appn. No. 60/636,663, filed December 15, 2004, entitled FcγRIIB-Specific Antibodies and Methods of Use Thereof; and U.S. Prov. Appn. No. 60/654,713, filed February 18, 2005, entitled "FcγRIIB-Specific Antibodies and Methods of Use Thereof," each of which is incorporated by reference herein in its entirety.

[00259] The compounds identified in accordance with the invention can be adminsitered to a subject as a pharmaceutical composition. The prophylactic or therapeutic agents of the combination therapies can be administered to a subject in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.

[00260] In a specific embodiment, a pharmaceutical composition comprising one or more compounds identified in an assay described herein is administered to a subject, preferably a human, to prevent, treat, manage or ameliorate cancer or a symptom thereof. In accordance with the invention, the pharmaceutical composition may also comprise one or more prophylactic or therapeutic agents. Preferably, such agents are currently being used, have been used or are known to be useful in the prevention, treatment, management or amelioration of cancer or a symptom thereof.

[00261] A compound identified in accordance with the methods of the invention may be used as any line of therapy (e.g., a first, second, third, fourth or fifth line of therapy) for cancer. The invention provides methods for treating, managing or ameliorating cancer or a symptom thereof in a subject refractory to conventional therapies for cancer, said methods comprising administering to said subject a dose of a prophylactically or therapeutically effective amount of a compound identified in accordance with the methods of the invention. [00262] The invention also encompasses methods for administering one or more compounds identified by the methods of the invention to treat or ameliorate symptoms in refractory patients. In a certain embodiment, that a cancer is refractory to a therapy means that at least some significant portion of the cancer cells are not killed or their cell division arrested. The determination of whether the cancer cells are refractory can be made either in vivo or in vitro by any method known in the art for assaying the effectiveness of treatment on cancer cells, using the art-accepted meanings of "refractory" in such a context. In various embodiments, a cancer is refractory where the number of cancer cells has not been significantly reduced, or has increased. The invention also encompasses methods for administering one or more compounds identified by the methods to prevent the onset or recurrence of cancer in patients predisposed to having cancer.

[00263] In particular embodiments, the compounds identified by the methods of the invention, or other therapies that reduce the expression of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib, are administered to reverse resistance or reduced sensitivity of cancer cells to certain hormonal, radiation and chemotherapeutic agents thereby resensitizing the cancer cells to one or more of these agents, which can then be administered (or continue to be administered) to treat or manage cancer, including to prevent metastasis.

[00264] The invention provides methods for treating, managing or ameliorating cancer or a symptom thereof in a subject refractory to existing single agent therapies for cancer, said methods comprising administering to said subject a dose of a prophylactically or therapeutically effective amount of a compound identified in accordance with the methods of the invention and a dose of a prophylactically or therapeutically effective amount of one or more other therapies (e.g., prophylactic or therapeutic agents). The invention also provides methods for treating or managing a cancer by administering a compound identified in accordance with the methods of the invention in combination with any other therapy (e.g., surgery) to patients who have proven refractory to other therapies but are no longer on these therapies.

[00265] In certain embodiments, the patients being treated by the methods of the invention are patients already being treated with chemotherapy, radiation therapy, hormonal therapy, or biological therapy/immunotherapy. Among these patients are refractory patients and those with cancer despite treatment with existing cancer therapies. In other embodiments, the patients have been treated and have no disease activity and one or more compounds of the invention are administered to prevent the recurrence of cancer. [00266] In preferred embodiments, the existing therapy is chemotherapy. In particular embodiments, the existing therapy includes administration of chemotherapies including, but not limited to, methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposides, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, etc. Among these patients are patients treated with radiation therapy, hormonal therapy and/or biological therapy/immunotherapy. Also among these patients are those who have undergone surgery for the treatment of cancer.

[00267] Alternatively, the invention also encompasses methods for treating patients undergoing or having undergone radiation therapy. Among these are patients being treated or previously treated with chemotherapy, hormonal therapy and/or biological therapy/immunotherapy. Also among these patients are those who have undergone surgery for the treatment of cancer.

[00268] In other embodiments, the invention encompasses methods for treating patients undergoing or having undergone hormonal therapy and/or biological therapy/immunotherapy. Among these are patients being treated or having been treated with chemotherapy and/or radiation therapy. Also among these patients are those who have undergone surgery for the treatment of cancer.

[00269] Additionally, the invention also provides methods of treatment of cancer as an alternative to chemotherapy, radiation therapy, hormonal therapy, and/or biological therapy/immunotherapy where the therapy has proven or may prove too toxic, i.e., results in unacceptable or unbearable side effects, for the subject being treated. The subject being treated with the methods of the invention may, optionally, be treated with other cancer treatments such as surgery, chemotherapy, radiation therapy, hormonal therapy or biological therapy, depending on which treatment was found to be unacceptable or unbearable.The invention also provides methods for the treatment or management of a patient having cancer and immunosuppressed by reason of having previously undergone other therapies. [00270] Specific examples of cancers that can be treated by the methods encompassed by the invention include, but are not limited to, cancers of the prostate, ovary, lung, colon, pancreas and bladder. Additional cancers are listed by example and not by limitation below. In particular embodiments, methods of the invention can be used to treat, manage and/or prevent metastasis from primary tumors.

[00271] The methods and compositions of the invention comprise the administration of one or more compounds identified by the methods of the invention to subjects/patients suffering from or expected to suffer from cancer, e.g., have a genetic predisposition for a particular type of cancer, have been exposed to a carcinogen, or are in remission from a particular cancer. Such patients may or may not have been previously treated for cancer. Included in the invention is also the treatment of patients undergoing other cancer therapies and the methods and compositions of the invention can be used before any adverse effects or intolerance of these other cancer therapies occurs.

5.6.1 CANCERS

[00272] Cancers and related disorders that can be treated, managed, prevented or ameliorated in accordance with the invention include, but are not limited to cancers of epithelial origin, endothelial origin, etc. Non-limiting examples of such cancers include the following: leukemias, such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias, such as, myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia leukemias and myelodysplastic syndrome; chronic leukemias, such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as but not limited to bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget' s disease, and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget' s disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma; gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell carcinoma, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/ or uterer); Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas (for a review of such disorders, see Fishman et al, 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

[00273] Accordingly, the methods and compositions of the invention are also useful in the treatment or prevention of a variety of cancers or other abnormal proliferative diseases, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyoscarcoma; other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarama, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma. It is also contemplated that cancers caused by aberrations in apoptosis would also be treated by the methods and compositions of the invention. Such cancers may include but not be limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis, and myelodysplastic syndromes. In specific embodiments, malignancy or dysproliferative changes (such as metaplasias and dysplasias), are treated, managed, or prevented in the prostate, ovary, lung, colon, pancreas, and/or bladder.

[00274] In particular embodiments, the cancer is malignant and overexpresses one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib.

[00275] In specific embodiments, the methods and compositions of the invention are used for the treatment, management and/or prevention of cancers of the prostate, ovary, lung, colon, pancreas and bladder and are provided below by example rather than by limitation.

5.6.1.1 TREATMENT OFCOLONCANCER

[00276] In specific embodiments, patients with colon cancer are administered an effective amount of one or more compounds identified by the methods of the invention. In another embodiment, the compounds identified by the methods of the invention are administered in combination with an effective amount of one or more other therapies useful for colon cancer therapy including but not limited to: the combination of 5-FU and leucovorin, the combination of 5-FU and levamisole, irinotecan (CPT-11) or the combination of irinotecan, 5-FU and leucovorin (IFL).

[00277] In a specific embodiment, the compositions and methods of the invention used to prevent, manage or treat colon cancer the expression and/or activity of a gene product of one or both of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, OR4M1 or KIAAl 679.

5.6.1.2 TREATMENT OF PROSTATE CANCER [00278] In specific embodiments, patients with prostate cancer are administered an effective amount of one or more compounds identified by the methods of the invention. In another embodiment, the compounds identified by the methods of the invention can be administered in combination with an effective amount of one or more other therapies useful for prostate cancer therapy including but not limited to: external-beam radiation therapy, interstitial implantation of radioisotopes (i.e., I , palladium, iridium), leuprolide or other LHRH agonists, non-steroidal antiandrogens (flutamide, nilutamide, bicalutamide), steroidal antiandrogens (cyproterone acetate), the combination of leuprolide and flutamide, estrogens such as DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens U.S.P., DES- diphosphate, radioisotopes, such as strontium-89, the combination of external-beam radiation therapy and strontium-89, second-line hormonal therapies such as aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, and ketoconazole, low-dose prednisone, or other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level including docetaxel, paclitaxel, estramustine/docetaxel, estramustine/etoposide, estramustine/vinblastine, and estramustine/paclitaxel. [00279] In a specific embodiment, the compositions and methods of the invention used to prevent, manage or treat prostate cancer target the expression and/or activity of a gene product of one or more of the following genes: TM9SF4, DC2, VAPB, TACSTD2, FNDC3A, GKOOl, SDFRl, ARP5 Long, ARP5 Short, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797 or MGC26856.

5.6.1.3 TREATMENT OF OVARIANCANCER

[00280] In specific embodiments, patients with ovarian cancer are administered an effective amount of one or more compounds identified by the methods of the invention. In another embodiment, the compounds identified by the methods of the invention can be administered in combination with an effective amount of one or more other therapies useful for ovarian cancer therapy including but not limited to: intraperitoneal radiation therapy, such as P³² therapy, total abdominal and pelvic radiation therapy, cisplatin, the combination of paclitaxel (Taxol) or docetaxel (Taxotere) and cisplatin or carboplatin, the combination of cyclophosphamide and cisplatin, the combination of cyclophosphamide and carboplatin, the combination of 5-FU and leucovorin, etoposide, liposomal doxorubicin, gemcitabine or topotecan. [00281] In a specific embodiment, the compositions and methods of the invention used to prevent, manage or treat ovarian cancer target the expression and/or activity of a gene product of one or more of the following genes and their protein products: TM9SF4, DC2, XTP3TPB, TACSTD2, FNDC3A, GKOOl, PROl 855, C20orf3, SDFRl, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJl 4681, C20orf22, FLJ14281_} FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP or FAD 104.

5.6.1.4 TREATMENT OF LUNG CANCER

[00282] In specific embodiments, patients with small lung cell cancer are administered an effective amount of one or more compounds identified by the methods of the invention. In another embodiment, the compounds identified by the methods of the invention can be administered in combination with an effective amount of one or more other therapies useful for lung cancer therapy including but not limited to: thoracic radiation therapy, cisplatin, vincristine, doxorubicin, and etoposide, alone or in combination, the combination of eye lophosphamide, doxorubicin, vincristine/etoposide, and cisplatin (CAV/EP), local palliation with endobronchial laser therapy, endobronchial stents, and/or brachytherapy. [00283] In other specific embodiments, patients with non-small lung cell cancer are administered an effective amount of one or more compounds identified by the methods of the invention in combination with an effective amount of one or more other therapies useful for lung cancer therapy including but not limited to: palliative radiation therapy, the combination of cisplatin, vinblastine and mitomycin, the combination of cisplatin and vinorelbine, paclitaxel, docetaxel or gemcitabine, the combination of carboplatin and paclitaxel, interstitial radiation therapy for endobronchial lesions or stereotactic radiosurgery. [00284] In a specific embodiment, the compositions and methods of the invention used to prevent, manage or treat lung cancer target the expression and/or activity of a gene product of one or more of the following genes and their protein products: TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ12443, FLJ20481, LENG4, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1 or GRIA4.

5.6.1.5 TREATMENT OFPANCREATIC CANCER

[00285] In specific embodiments, patients with pancreatic cancer are administered an effective amount of one or more compounds identified by the methods of the invention. In another embodiment, the compounds identified by the methods of the invention can be administered in combination with an effective amount of one or more other therapies useful for pancreatic cancer therapy including but not limited to: chemotherapy, including, but not limited to, 5-fluorouracil (5-FU) and gemcitabine; surgery, including but not limited to pancreaticoduodenectomy (Whipple procedure), distal pancreatectomy, total pancreatectomy; palliative procedures; and radiation therapy.

[00286] In a specific embodiment, the compositions and methods of the invention used to prevent, manage or treat pancreatic cancer target the expression and/or activity of a gene product of one or more of the following gene and its protein products: TMD0645.

5.6.1.6TREATMENT OFBLADDERCANCER

[00287] In specific embodiments, patients with bladder cancer are administered an effective amount of one or more compounds identified by the methods of the invention. In another embodiment, the compounds identified by the methods of the invention can be administered in combination with an effective amount of one or more other therapies useful for bladder cancer therapy including but not limited to chemotherapy, including, but not limited to, cisplatin, cyclophosphamide, doxorubicin, methotrexate and/or vinblastin. [00288] In a specific embodiment, the compositions and methods of the invention used to treat bladder cancer target the expression and/or activity of the UPK-Ib gene. In another specific embodiment, the compositions and methods of the invention used to prevent, manage or treat bladder cancer do not target the expression and/or activity of the UPK-Ib gene.

5.6.2 COMPOUNDS FOR USE IN PREVENTING, TREATING, MANAGING OR AMELIORATING CANCER OR A SYMPTOM THEREOF

[00289] Representative, non-limiting examples of compounds that can used in accordance with the methods of the invention to prevent, treat, manage and/or ameliorate cancer or a symptom thereof are described in detail below.

[00290] First, such compounds can include, for example, antisense, ribozyme, or triple helix compounds that can downregulate the expression and/or activity of a gene product of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FADl 04, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. Such compounds are described in detail in the subsection below. [00291] Second, such compounds can include, for example, antibody compositions that can modulate the expression and/or activity of a gene product of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAAl 679 and/or UPK-Ib. [00292] Third, such compounds can include, for example, SLC12A2, FLJ23375,

GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAAl 679 and/or UPK-Ib proteins or protein fragments. The invention encompasses the use of peptides or peptide mimetics selected to mimic SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib protein to prevent, treat, manage or ameliorate cancer or a symptom thereof. Further, such compounds can include, for example, dominant- negative polypeptides that can modulate the expression and/or activity of proteins encoded by one or more of the following genes: SLCl 2 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib.

[00293] The methods also encompasses the use of derivatives, analogs and fragments of an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein to prevent, treat, manage or ameliorate cancer or a symptom thereof. In particular, the invention encompasses the use of fragments of an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein comprising one or more domains of such a protein(s) to prevent, treat, manage or ameliorate cancer or a symptom thereof. In another specific embodiment, the invention encompasses the use of an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRJA4, OR4M1, KIAAl 679 and/or UPK-Ib protein, analog, derivative or fragment thereof which is expressed as a fusion, or chimeric protein product (comprising the protein, fragment, analog, or derivative joined via a peptide bond to a heterologous protein sequence).

[00294] In specific embodiments, SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2,

C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib antisense oligonucleotides or any combination thereof, are administered to prevent, treat, manage or ameliorate cancer (e.g., prostate cancer, ovarian cancer, lung cancer, colon cancer, pancreatic cancer, or bladder cancer) or a symptom thereof. In other embodiments, a protein or fragment thereof encoded by one or more of the following genes is administered to prevent, treat, manage or ameliorate cancer or a symptom thereof: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. [00295] In other embodiments, one or more anti-SLC12A2, anti-FLJ23375, anti-

GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti- TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti- MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti- FLJ90709, anti-VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl 8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti- SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti- TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti- SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti- C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATP10B, anti-PTK7, anti-FLJ 14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OS AP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti- RON, anti-ATP13Al, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti- KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof. In a specific embodiment, said antibodies are polyclonal antibodies. In another specific embodiment, said antibodies are monoclonal antibodies. [00296] In other embodiments, one or more SLC12A2, FLJ23375, GRM5, TAS2R1,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib dominant-negative polypeptides are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof. 5.6.2.1 ANTISENSE, RIBOZYME, TRIPLE-HELIX, RNAi COMPOSITIONS

[00297] The present invention provides for the production of nucleic acid compositions, including but not limited to, antisense, ribozyme, triple-helix and RNAi compositions for the prevention, treatment, management and amelioration of cancer. The methods of the invention also comprise the administration of an effective amount of one or more nucleic acid compositions of the invention that modulate the expression and/or activity of one or more cancer targets disclosed herein (e.g., one or more cancer targets disclosed in Table 1, supra) for the prevention, treatment, management and amelioration of cancer. [00298] Standard techniques can be utilized to produce antisense, triple helix, or ribozyme molecules for use as part of the methods described herein. First, standard techniques can be utilized for the production of antisense nucleic acid molecules, i.e., molecules which are complementary to a sense nucleic acid encoding a polypeptide of interest (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJl 4681, C20orf22, FLJl 4281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib polypeptide), e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence, based on sequences that are provided in, e.g., Table 1, supra, or sequences that are publicly available (e.g., published sequences or available through a sequence database such as GenBank). Accordingly, an antisense nucleic acid can hydrogen bond to a sense nucleic acid. The antisense nucleic acid can be complementary to an entire coding strand, or to only a portion thereof, e.g., all or part of the protein coding region (or open reading frame). An antisense nucleic acid molecule can be antisense to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding a polypeptide of interest. The non-coding regions ("5' and 3' untranslated regions") are the 5' and 3' sequences that flank the coding region and are not translated into amino acids. [00299] An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30,

35, 40, 45 or 50 nucleotides or more in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid {e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Examples of modified nucleotides which can be used to generate the antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil,

5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5 -methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil,

3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation {i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest). [00300] Antisense nucleic acid molecules administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA encoding the polypeptide of interest to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule which binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue, e.g., transplant or autoimmune lesion, site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell, e.g., prostate, ovary, lung, colon, pancreas or bladder cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. The antisense nucleic acid molecules can also be delivered to cells using vectors, e.g., gene therapy vectors, described below. To achieve sufficient intracellular concentrations of the antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred. [00301] An antisense nucleic acid molecule of interest can be an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual α-units, the strands run parallel to each other (Gaultier et al. (1987) Nucleic Acids Res. 15:6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (Inoue et al. (1987) Nucleic Acids Res. 15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et al. (1987) FEBS Lett. 215:327-330).

[00302] Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region, and can also be generated using standard techniques. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. A ribozyme having specificity for a nucleic acid molecule encoding a polypeptide of interest can be designed based upon the nucleotide sequence of a cDNA disclosed herein. For example, a derivative of a Tetrahymena L- 19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a Cech et al. U.S. Patent No. 4,987,071; and Cech et al. U.S. Patent No. 5,116,742. Alternatively, an mRNA encoding a polypeptide of interest can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel and Szostak (1993) Science 261:1411-1418. [00303] Triple helical structures can also be generated using well known techniques.

For example, expression of a polypeptide of interest can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the polypeptide {e.g., the promoter and/or enhancer) to form triple helical structures that prevent transcription of the gene in target cells. See generally Helene (1991) Anticancer Drug Des. 6(6):569-84; Helene (1992) Ann. NY. Acad. ScI 660:27-36; and Maher (1992) Bioassays 14(12):807-15. [00304] In various embodiments, nucleic acid compositions can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorganic & Medicinal Chemistry 4(1): 5-23). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. ScL USA 93: 14670-675.

[00305] PNAs can, for example, be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras can be generated which may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes, e.g., RNAse H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup (1996), supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996), supra, and Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs. Compounds such as 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al. (1989) Nucleic Acids Res. 17:5973-88). PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63). Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al. (1975) Bioorganic Med. Chem. Lett. 5:1119-11124). [00306] In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo ), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al. (1989) Proc. Natl. Acad. ScL USA 86:6553-6556; Lemaitre et al. (1987) Proc. Natl. Acad. Sci. USA 84:648-652; PCT Publication No. WO 88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al. (1988) Bio/Techniques 6:958-976) or intercalating agents (see, e.g., Zon (1988) Pharm. Res. 5:539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc. [00307] In certain embodiments, an RNA interference (RNAi) molecule is used to decrease expression of protein or protein of interest (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib protein). RNAi is defined as the ability of double-stranded RNA (dsRNA) to suppress the expression of a gene corresponding to its own sequence. RNAi is also called post-transcriptional gene silencing or PTGS. Since the only RNA molecules normally found in the cytoplasm of a cell are molecules of single-stranded mRNA, the cell has enzymes that recognize and cut dsRNA into fragments containing 21-25 base pairs (approximately two turns of a double helix). The antisense strand of the fragment separates enough from the sense strand so that it hybridizes with the complementary sense sequence on a molecule of endogenous cellular mRNA (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATPl 3Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib mRNA). This hybridization triggers cutting of the mRNA in the double-stranded region, thus destroying its ability to be translated into a polypeptide. Introducing dsRNA corresponding to a particular gene thus knocks out the cell's own expression of that gene in particular tissues and/or at a chosen time. [00308] Double-stranded (ds) RNA can be used to interfere with gene expression in mammals (Wianny & Zernicka-Goetz, 2000, Nature Cell Biology 2:10-15\ incorporated herein by reference in its entirety). dsRNA is used as inhibitory RNA or RNAi of the function of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib to produce a phenotype that is the same as that of a null mutant of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib (Wianny & Zernicka-Goetz, 200O, Nature Cell Biology 2: 70-75). In certain embodiments, dsDNA encoding dsRNA (e.g., as hairpin structures) is used to express RNAi- mediating dsDNA in the cell.

5.6.2.2 ANTIBODY COMPOSITIONS

[00309] In one embodiment, an antibody that immunospecifically binds to an

SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein or fragment thereof is administered to a subject, preferably, a human, to prevent, treat, manage or ameliorate cancer or a symptom thereof. In another embodiment, any combination of anti- SLCl 2 A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti- MGC15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti- NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti- PLVAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDlLl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti- CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti- VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti- PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti- ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti- ATPlOB, anti-PTK7, anti-FLJ 14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti- TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti- FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti-ATP13Al, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti- GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies are administered to a subject, preferably a human, to prevent, treat, manage or ameliorate cancer or a symptom thereof.

[00310] In a specific embodiment, anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-

TAS2R1, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti- KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti- BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies are administered to a subject preferably a human, in combination with other types of therapies {e.g., cancer therapies) to prevent, treat, manage or ameliorate cancer or a symptom thereof.

[00311] Anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-

C14orfl60, anti-MGC15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti- GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti-VEZATIN, anti-TMPRSS9, anti- ATP13A5, anti-PKHDILl, anti-C2orfl 8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-0CIAD2, anti- PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti- ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti- ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti- TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti- FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti-ATP13Al, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti- GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies or any combination thereof can be administered to a subject, preferably a human, using various delivery systems are known to those of skill in the art. For example, anti-SLC12A2, anti-FLJ23375, anti- GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti- TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti- MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti- FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti- SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti- TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti- SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti- C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti- RON, anti-ATP13Al, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti- KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies, or any combination thereof, can be administered by encapsulation in liposomes, microparticles or microcapsules. See, e.g., U.S. Patent No. 5,762,904, U.S. Patent No. 6,004,534, and PCT Publication WO 99/52563. In addition, anti-SLC12A2, anti- FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC15668, anti- MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti- BAT2D1, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti- FLJ31528, anti-FLJ90709, anti-VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti- SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti-TM9SF4, anti~DC2, anti-VAPB, anti- XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-0CIAD2, anti-PRO1855, anti- C20orf3, anti-SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti-ARP5 Long, anti- ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti- FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti- ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti- SLC27A3, anti-RON, anti-ATP13Al, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti- KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti- KIAAl 679 and/or anti-UPK-lb antibodies, or any combination thereof, can be administered using recombinant cells capable of expressing the antibodies, or retroviral, other viral vectors or non- viral vectors capable of expressing the antibodies.

[00312] Anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-

C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti- GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti-VEZATIN, anti-TMPRSS9, anti- ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti- PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti- ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti- ATPlOB, anti-PTK7, anti-FLJ 14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti- TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti- FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti-ATP13Al, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti- GRIA, anti-OR4Ml, anti-KlAA1679 and/or anti-UPK-lb antibodies can be obtained from any known source. Alternatively, anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti- TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl 8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti- TM9SF4, anti-DC2, anti- VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti- GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ 12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ 14681, anti-C20or£22, anti- FLJ 14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques. [00313] In a specific embodiment, antibodies of the invention bind to an extracellular domain of any one or combination of the following proteins: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib.

[00314] Antibodies include, but are not limited to, polyclonal antibodies, monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, single-chain Fvs (scFv), single chain antibodies, single domain antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), and anti- idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope-binding fragments of any of the above. The term "antibody", as used herein, refers to immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding site. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG₁, IgG₂, IgG₃, IgG₄, IgA₁ and IgA₂) or subclass. Examples of immunologically active fragments of immunoglobulin molecules include F(ab) and F(ab')2 fragments which can be generated by treating the antibody with an enzyme such as pepsin or papain. [00315] Antibodies that immunospecifically bind to an antigen can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques.

[00316] Polyclonal antibodies that immunospecifically bind to an antigen can be produced by various procedures well-known in the art. For example, a human antigen can be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the human antigen. Various adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyam^'ons, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette- Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art. [00317] Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al. , Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al, in: Monoclonal Antibodies and T-CeIl Hybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporated by reference in their entireties). The term "monoclonal antibody" as used herein is not limited to antibodies produced through hybridoma technology. The term "monoclonal antibody" refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.

[00318] In a specific embodiment, of the invention comprises a variant Fc region with enhanced activity (see U.S. Appn. Nos. 10/902,588, filed July 28, 2004; 10/754,922, filed January 9, 2004; 60/514,549, filed October 23, 2003; 60/456,041, filed March 19, 2003; and 60/439,498, filed January 9, 2003, all entitled "Identification and Engineering of Antibodies With Variant Fc Regions and Methods of Using Same," and each of which is incorporated by reference herein in its entirety). In accordance with this embodiment, the modified Fc region binds to activating receptors on immune effector cells (e.g., macrophages, natural killer cells, B-cells and/or neutrophils) with greater selectivity and affinity to enhance effector cell response. In specific embodiments, the receptors on the effector cells are CD16A and/or CD32A. In other specific embodiments, the receptors on the effector cells are not CD16A or CD32A.

[00319] Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art. Briefly, mice can be immunized with SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3_? SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein or a fragment thereof, and once an immune response is detected, e.g., antibodies specific for the protein are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution. Additionally, a RIMMS (repetitive immunization multiple sites) technique can be used to immunize an animal (Kilptrack et al, 1997 Hybridoma 16:381-9, incorporated by reference in its entirety). The hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention. Ascites fluid, which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.

[00320] Accordingly, the present invention provides methods of generating antibodies by culturing a hybridoma cell secreting an antibody of the invention wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with SLC12A2, FLJ23375, GRM5, TAS2R1 , NRXN2, C14orfl60, MGC15668, MGC33486, TMEMl 6F, FAT, KIAAO 195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein or a fragment thereof, with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind to the protein or protein fragment. [00321] Antibody fragments which recognize specific epitopes of SLC 12A2,

FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJl 4681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib protein may be generated by any technique known to those of skill in the art. In a specific embodiment, the epitopes are located in an extracellular domain of SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl. SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. For example, Fab and F(ab')2 fragments of the invention may be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments). F(ab')₂ fragments contain the variable region, the light chain constant region and the CHl domain of the heavy chain. Further, the antibodies of the present invention can also be generated using various phage display methods known in the art.

[00322] In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them. In particular, DNA sequences encoding VH and VL domains are amplified from animal cDNA libraries (e.g., human or murine cDNA libraries of affected tissues). The DNA encoding the VH and VL domains are recombined together with an scFv linker by PCR and cloned into a phagemid vector. The vector is electroporated in E. coli and the E. coli is infected with helper phage. Phage used in these methods are typically filamentous phage including fd and Ml 3 and the VH and VL domains are usually recombinantly fused to either the phage gene III or gene VIII. Phage expressing an antigen binding domain that binds to a particular antigen can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkman et al., 1995, J. Immunol. Methods 182:41-50; Ames et al., 1995, J. Immunol. Methods 184:177- 186; Kettleborough et al. , 1994, Eur. J. Immunol. 24:952-958; Persic et al., 1997, Gene 187:9-18; Burton et al., 1994, Advances in Immunology 57:191-280; PCT Application No. PCT/GB91/O1 134; International Publication Nos. WO 90/02809, WO 91/10737, WO 92/01047, WO 92/18619, WO 93/1 1236, WO 95/15982, WO 95/20401, and WO97/13844; and U.S. Patent Nos. 5,698,426, 5,223,409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727, 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety. [00323] As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described below. Techniques to recombinantly produce Fab, Fab' and F(ab')₂ fragments can also be employed using methods known in the art such as those disclosed in PCT publication No. WO 92/22324; Mullinax et al., 1992, BioTechniques 12(6):864-869; Sawai et al., 1995, AJRI 34:26-34; and Better et al., 1988, Science 240:1041-1043 (said references incorporated by reference in their entireties).

[00324] To generate whole antibodies, PCR primers including VH or VL nucleotide sequences, a restriction site, and a flanking sequence to protect the restriction site can be used to amplify the VH or VL sequences in scFv clones. Utilizing cloning techniques known to those of skill in the art, the PCR amplified VH domains can be cloned into vectors expressing a VH constant region, e.g. , the human gamma 4 constant region, and the PCR amplified VL domains can be cloned into vectors expressing a VL constant region, e.g., human kappa or lamba constant regions. Preferably, the vectors for expressing the VH or VL domains comprise an EF- lα promoter, a secretion signal, a cloning site for the variable domain, constant domains, and a selection marker such as neomycin. The VH and VL domains may also cloned into one vector expressing the necessary constant regions. The heavy chain conversion vectors and light chain conversion vectors are then co-transfected into cell lines to generate stable or transient cell lines that express full-length antibodies, e.g., IgG, using techniques known to those of skill in the art.

[00325] For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use human or chimeric antibodies. Completely human antibodies are particularly desirable for therapeutic treatment of human subjects. Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also U.S. Patent Nos. 4,444,887 and 4,716,111; and International Publication Nos. WO 98/46645, WO 98/50433, WO 98/24893, WO98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.

[00326] Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JJJ region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then be bred to produce homozygous offspring which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publication Nos. WO 98/24893, WO 96/34096, and WO 96/33735; and U.S. Patent Nos. 5,413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,939,598, which are incorporated by reference herein in their entirety. In addition, companies such as Abgenix, Inc. (Fremont, CA) and Genpharm (San Jose, CA) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above. [00327] A chimeric antibody is a molecule in which different portions of the antibody are derived from different immunoglobulin molecules. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, 1985, Science 229:1202; Oi et al, 1986, BioTechniques 4:214; Gillies et al., 1989, J. Immunol. Methods 125:191-202; and U.S. Patent Nos. 5,807,715, 4,816,567, 4,816,397, and 6,331,415, which are incorporated herein by reference in their entirety.

[00328] A humanized antibody is an antibody or its variant or fragment thereof which is capable of binding to a predetermined antigen and which comprises a framework region having substantially the amino acid sequence of a human immunoglobulin and a CDR having substantially the amino acid sequence of a non-human immuoglobulin. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')₂, Fabc, Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. Preferably, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Ordinarily, the antibody will contain both the light chain as well as at least the variable domain of a heavy chain. The antibody also may include the CHl, hinge, CH2, CH3, and CH4 regions of the heavy chain. The humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG₁, IgG₂, IgG₃ and IgG₄. Usually the constant domain is a complement fixing constant domain where it is desired that the humanized antibody exhibit cytotoxic activity, and the class is typically IgG₁. Where such cytotoxic activity is not desirable, the constant domain may be of the IgG₂ class. The humanized antibody may comprise sequences from more than one class or isotype, and selecting particular constant domains to optimize desired effector functions is within the ordinary skill in the art. The framework and CDR regions of a humanized antibody need not correspond precisely to the parental sequences, e.g., the donor CDR or the consensus framework may be mutagenized by substitution, insertion or deletion of at least one residue so that the CDR or framework residue at that site does not correspond to either the consensus or the import antibody. Such mutations, however, will not be extensive. Usually, at least 75% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences, more often 90%, and most preferably greater than 95%. Humanized antibody can be produced using variety of techniques known in the art, including but not limited to, CDR-grafting (European Patent No. EP 239,400; International publication No. WO 91/09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology 28(4/5):489-498; Studnicka et al, 1994, Protein Engineering 7(6):805-814; and Roguska et al. , 1994, PNAS 91:969-973), chain shuffling (U.S. Patent No. 5,565,332), and techniques disclosed in, e.g ., U.S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, WO 9317105, Tan et al., J. Immunol. 169:1119-25 (2002), Caldas et al., Protein Eng. 13(5):353 - 60 (2000), Morea et al., Methods 20(3):267-79 (2000), Baca et al., J. Biol. Chem. 272(16):10678-84 (1997), Roguska et al., Protein Eng. 9(10):895-904 (1996), Couto et al., Cancer Res. 55 (23 Suρp):5973s - 5977s (1995), Couto et al., Cancer Res. 55(8):1717-22 (1995), Sandhu JS, Gene 150(2):409-10 (1994), and Pedersen et al., J. MoI. Biol. 235(3):959-73 (1994). Often, framework residues in the framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Patent No. 5,585,089; and Riechmann et al., 1988, Nature 332:323, which are incorporated herein by reference in their entireties.)

[00329] Single domain antibodies, for example, antibodies lacking the light chains, can be produced by methods well-known in the art. See Riechmann et al., 1999, J. Immuno. 231:25-38; Nuttall et al., 2000, Curr. Pharm. Biotechnol. l(3):253-263; Muylderman, 2001, J. Biotechnol. 74(4):277302; U.S. Patent No. 6,005,079; and International Publication Nos. WO 94/04678, WO 94/25591, and WO 01/44301, each of which is incorporated herein by reference in its entirety.

[00330] Further, the antibodies that immunospecifϊcally bind to an antigen (e.g.,

SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FADl 04, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib protein or a fragment thereof) can, in turn, be utilized to generate anti-idiotype antibodies that "mimic" an antigen using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, 1989, FASEB J. 7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). [00331] The invention encompasses polynucleotides comprising a nucleotide sequence encoding an antibody or fragment thereof that immunospecifically binds to an antigen (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib protein or a fragment thereof). The invention also encompasses polynucleotides that hybridize under high stringency, intermediate or lower stringency hybridization conditions to polynucleotides that encode an antibody of the invention.

[00332] The polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. The nucleotide sequences encoding known antibodies can be determined using methods well known in the art, i.e., nucleotide codons known to encode particular amino acids are assembled in such a way to generate a nucleic acid that encodes the antibody. Such a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al, 1994, BioTechniques 17:242), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, fragments, or variants thereof, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR. [00333] Alternatively, a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody of the invention) by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR may then be cloned into replicable cloning vectors using any method well known in the art.

[00334] Once the nucleotide sequence of the antibody is determined, the nucleotide sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY, which are both incorporated by reference herein in their entireties), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.

[00335] Once a polynucleotide encoding an antibody molecule, heavy or light chain of an antibody, or fragment thereof (preferably, but not necessarily, containing the heavy or light chain variable domain) of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well-known in the art. Once an antibody molecule has been produced by recombinant expression, it may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, the antibodies or fragments thereof may be fused to heterologous polypeptide sequences known in the art to facilitate purification.

5.6.2.3 ANTIBODY CONJUGATES [00336] The present invention encompasses the use of compounds identified by the methods of the invention (e.g., anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti- TMPRSS9, anti-ATP13A5, anti-PKHDlLl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti- TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti- GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies) that are recombinantly fused or chemically conjugated (including both covalent and non-covalent conjugations) to a heterologous protein or polypeptide (or fragment thereof, preferably to a polypeptide of at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids) to generate fusion proteins. For example, antibodies may be used to target heterologous polypeptides to particular cell types, either in vitro or in vivo, by fusing or conjugating the antibodies to antibodies specific for particular surface proteins, e.g., cell surface receptors. Antibodies fused or conjugated to heterologous polypeptides may also be used in in vitro immunoassays and purification methods using methods known in the art. See e.g., International Publication WO 93/21232; EP 439,095; Naramura et al., 1994, Immunol. Lett. 39:91-99; U.S. Patent 5,474,981; Gillies et al., 1992, PNAS 89:1428-1432; and Fell et al., 1991, J. Immunol. 146:2446-2452, which are incorporated by reference in their entireties. [00337] The present invention further includes compositions comprising heterologous polypeptides fused or conjugated to antibody fragments. For example, the heterologous polypeptides may be fused or conjugated to a Fab fragment, Fd fragment, Fv fragment, F(ab)₂ fragment, or portion thereof. Methods for fusing or conjugating proteins, polypeptides, or peptides to an antibody or an antibody fragment are known in the art. See, e.g., U.S. Patent Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946; European Patent Nos. EP 307,434 and EP 367,166; International Publication Nos. WO 96/04388 and WO 91/06570; Ashkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88: 10535-10539; Zheng et al., 1995, J. Immunol. 154:5590-5600; and ViI et al., 1992, Proc. Natl. Acad. Sci. USA 89:11337- 11341 (said references are incorporated herein by reference in their entireties). [00338] Additional fusion proteins may be generated through the techniques of gene- shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling (collectively referred to as "DNA shuffling"). DNA shuffling may be employed to alter the activities of antibodies of the invention (e.g. , antibodies with higher affinities and lower dissociation rates). See, generally, U.S. Patent Nos. 5,605,793; 5,811,238; 5,830,721; 5,834,252; and 5,837,458, and Patten et al., 1997, Curr. Opinion Biotechnol. 8:724-33; Harayama, 1998, Trends Biotechnol. 16:76; Hansson, et al., 1999, J. MoL Biol. 287:265; and Lorenzo and Blasco, 1998, BioTechniques 24:308 (each of these patents and publications are hereby incorporated by reference in its entirety). Antibodies, or the encoded antibodies, may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. One or more portions of a polynucleotide encoding an antibody, which portions immunospecifically bind to SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

[00339] Moreover, the antibodies can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., Chatsworth, CA), among others, many of which are commercially available. As described in Gentz et al., 1989, PNAS 86:821, for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the hemagglutinin "HA" tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., 1984, Cell 37:767) and the "flag" tag. [00340] In other embodiments, antibodies of the present invention or variants thereof are conjugated to a diagnostic or detectable agent. Such antibodies can be useful for monitoring or prognosing the development or progression of a cancer as part of a clinical testing procedure, such as determining the efficacy of a particular therapy. Additionally, such antibodies can be useful for monitoring or prognosing the development or progression of cancer. In a specific embodiment, an anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti- TAS2R1, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti- KIAA0685, anti-EDG3, anti-GGTL3, anti-PL VAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti- BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ 14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibody of the invention is conjugated to a diagnostic or detectable agent. [00341] Such diagnosis and detection can accomplished by coupling the antibody to detectable substances including, but not limited to various enzymes, such as but not limited to horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as but not limited to streptavidin/biotin and avidin/biotin; fluorescent materials, such as but not limited to, umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; luminescent materials, such as but not limited to, luminol; bioluminescent materials, such as but not limited to, luciferase, luciferin, and aequorin; radioactive materials, such as but not limited to, bismuth (²¹³Bi), carbon (¹⁴C), chromium (⁵¹Cr), cobalt (⁵⁷Co), fluorine (¹⁸F), gadolinium (¹⁵³Gd, ¹⁵⁹Gd), gallium (⁶⁸Ga, 67Ga), germanium (⁶⁸Ge), holmium (¹⁶⁶Ho), indium (¹¹⁵In, ¹¹³In, ¹¹²In, ¹¹¹In), iodine (¹³¹I, ¹²⁵1, 1231, ¹²¹I), lanthanium (¹⁴⁰La), lutetium (¹⁷⁷Lu), manganese (⁵⁴Mn), moly bdenum (⁹⁹Mo), palladium (¹⁰³Pd), phosphorous (³²P), praseodymium (¹⁴²Pr), promethium (¹⁴⁹Pm), rhenium Re,Re), rhodium Rh), ruthemium (⁹⁷Ru), samarium (153Sm), scandium (47Sc), selenium (75Se), strontium (85Sr), sulfur (³⁵S), technetium (⁹⁹Tc), thallium (²⁰¹Ti), tin (¹¹³Sn, ¹¹⁷Sn), tritium (³H), xenon (¹³³Xe), ytterbium (¹⁶⁹Yb, ¹⁷⁵Yb), yttrium Y), zinc (Zn); positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions. [00342] The present invention further encompasses uses of antibodies or fragments thereof conjugated to a prophylactic or therapeutic agent. An antibody or fragment thereof may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Therapeutic moieties include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine); alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BCNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cisdichlorodiamine platinum (II) (DDP), and cisplatin); anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin); antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)); Auristatin molecules (e.g., auristatin PHE, bryostatin 1, and solastatin 10; see Woyke et al., Antimicrob. Agents Chemother. 46:3802-8 (2002), Woyke et al., Antimicrob. Agents Chemother. 45:3580-4 (2001), Mohammad et al., Anticancer Drugs 12:735-40 (2001), Wall et al., Biochem. Biophys. Res. Commun. 266:76- 80 (1999), Mohammad et al., Int. J. Oncol. 15:367-72 (1999), all of which are incorporated herein by reference); hormones (e.g., glucocorticoids, progestins, androgens, and estrogens), DNA-repair enzyme inhibitors (e.g., etoposide or topotecan), kinase inhibitors (e.g., compound STl 571, imatinib mesylate (Kantarjian et al., Clin Cancer Res. 8(7):2167-76 (2002)); cytotoxic agents (e.g., paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1- dehydrotestosterone, glucorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof and those compounds disclosed in U.S. Pat. Nos. 6,245,759, 6,399,633, 6,383,790, 6,335,156, 6,271,242, 6,242,196, 6,218,410, 6,218,372, 6,057,300, 6,034,053, 5,985,877, 5,958,769, 5,925,376, 5,922,844, 5,911,995, 5,872,223, 5,863,904, 5,840,745, 5,728,868, 5,648,239, 5,587,459); farnesyl transferase inhibitors (e.g., Rl 15777, BMS-214662, and those disclosed by, for example, U.S. Patent Nos: 6,458,935, 6,451,812, 6,440,974, 6,436,960, 6,432,959, 6,420,387, 6,414,145, 6,410,541, 6,410,539, 6,403,581, 6,399,615, 6,387,905, 6,372,747, 6,369,034, 6,362,188, 6,342,765, 6,342,487, 6,300,501, 6,268,363, 6,265,422, 6,248,756, 6,239,140, 6,232,338, 6,228,865, 6,228,856, 6,225,322, 6,218,406, 6,211,193, 6,187,786, 6,169,096, 6,159,984, 6,143,766, 6,133,303, 6,127,366, 6,124,465, 6,124,295, 6,103,723, 6,093,737, 6,090,948, 6,080,870, 6,077,853, 6,071,935, 6,066,738, 6,063,930, 6,054,466, 6,051,582, 6,051,574, and 6,040,305); topoisomerase inhibitors (e.g., camptothecin; irinotecan; SN-38; topotecan; 9- aminocamptothecin; GG-211 (GI 147211); DX-8951f; IST-622; rubitecan; pyrazoloacridine; XR-5000; saintopin; UCE6; UCE1022; TAN-1518A; TAN-1518B; KT6006; KT6528; ED- 110; NB-506; ED-110; NB-506; and rebeccamycin); bulgarein; DNA minor groove binders such as Hoescht dye 33342 and Hoechst dye 33258; nitidine; fagaronine; epiberberine; coralyne; beta-lapachone; BC-4-1; bisphosphonates (e.g., alendronate, cimadronte, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate); HMG-CoA reductase inhibitors, (e.g., lovastatin, simvastatin, atorvastatin, pravastatin, fluvastatin, statin, cerivastatin, lescol, lupitor, rosuvastatin and atorvastatin); antisense oligonucleotides (e.g., those disclosed in the U.S. Pat. Nos. 6,277,832, 5,998,596, 5,885,834, 5,734,033, and 5,618,709); adenosine deaminase inhibitors (e.g., Fludarabine phosphate and 2-Chlorodeoxyadenosine); ibritumomab tiuxetan (Zevalin®); tositumomab (Bexxar®)) and pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In a specific embodiment, the prophylactic or therapeutic agent to be conjugated to an antibody of the invention is cytotoxic to a target cell (e.g., a prostate, ovary, lung, colon, pancreatic or bladder cell).

[00343] Moreover, an antibody can be conjugated to therapeutic moieties such as a radioactive materials or macrocyclic chelators useful for conjugating radiometal ions (see above for examples of radioactive materials). In certain embodiments, the macrocyclic chelator is 1,4,7, 10-tetraazacyclododecane-N, N', N", N"-tetraacetic acid (DOTA) which can be attached to the antibody via a linker molecule. Such linker molecules are commonly known in the art and described in Denardo et al., 1998, Clin Cancer Res. 4:2483-90; Peterson et al., 1999, Bioconjug. Chem. 10:553; and Zimmerman et al., 1999, Nucl. Med. Biol. 26:943-50 each incorporated by reference in their entireties.

[00344] Further, an antibody may be conjugated to a prophylactic or therapeutic moiety or drug moiety that modifies a given biological response. Therapeutic moieties or drug moieties are not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein, peptide, or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, cholera toxin, or diphtheria toxin; a protein such as tumor necrosis factor, α-interferon, γ-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-α, TNF-γ, AIM I (see, International Publication No. WO 97/33899), AIM II (see, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al., 1994, J. Immunol., 6:1567-1574), and VEGF (see, International Publication No. WO 99/23105), an anti-angiogenic agent, e.g., angiostatin, endostatin or a component of the coagulation pathway (e.g., tissue factor); or, a biological response modifier such as, for example, a lymphokine (e.g., interferon gamma ("IFN-γ"), interleukin-1 ("IL-I"), interleukin-2 ("IL-2"), interleukin-5 ("IL-5"), interleukin-6 ("IL-6"), interleuking-7 ("IL-7"), interleukin-10 ("IL-IO"), interleukin-12 ("IL-12"), interleukin-15 ("IL-15"), interleukin-23 ("IL-23"), granulocyte macrophage colony stimulating factor ("GM-CSF"), and granulocyte colony stimulating factor ("G-CSF")), or a growth factor (e.g., growth hormone ("GH")), or a coagulation agent (e.g., calcium, vitamin K, tissue factors, such as but not limited to, Hageman factor (factor XII), high-molecular- weight kininogen (HMWK), prekallikrein (PK), coagulation proteins-factors II (prothrombin), factor V, XIIa, VIII, XIIIa, XI, XIa,, IX, IXa, X, phospholipid fibrinopeptides A and B from the α and β chains of fibrinogen, fibrin monomer). In a specific embodiment, an antibody that immunospecifically binds to an IL-9 polypeptide is conjugated with a leukotriene antagonist (e.g., montelukast, zafirlukast, pranlukast, and zyleuton).

[00345] In another embodiment, antibodies can be fused or conjugated to liposomes, wherein the liposomes are used to encapsulate prophylactic or therapeutic agents (see e.g., Park et al., 1997, Can. Lett. 118:153-160; Lopes de Menezes et al., 1998, Can. Res. 58:3320- 30; Tseng et al., 1999, Int. J. Can. 80:723-30; Crosasso et al., 1997, J. Pharm. Sci. 86:832-9). In a preferred embodiment, the pharmokinetics and clearance of liposomes are improved by incorporating lipid derivatives of PEG into liposome formulations (see, e.g., Allen et al., 1991, Biochem Biophys Acta 1068:133-41; Huwyler et al., 1997, J. Pharmacol. Exp. Ther. 282:1541-6). [00346] Techniques for conjugating prophylactic or therapeutic moieties to antibodies are well known. Moieties can be conjugated to antibodies by any method known in the art, including, but not limited to aldehyde/Schiff linkage, sulphydryl linkage, acid-labile linkage, cis-aconityl linkage, hydrazone linkage, enzymatically degradable linkage (see generally Garnett, 2002, Adv. Drug Deliv. Rev. 53:171-216). Additional techniques for conjugating prophylactic or therapeutic moieties to antibodies are well known, see, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy," in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery," in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review," in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy, " in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303- 16 (Academic Press 1985), and Thorpe et al., 1982, Immunol. Rev. 62:119-58. Methods for fusing or conjugating antibodies to polypeptide moieties are known in the art. See, e.g., U.S. Patent Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946; EP 307,434; EP 367,166; International Publication Nos. WO 96/04388 and WO 91/06570; Ashkenazi et al., 1991, PNAS 88: 10535-10539; Zheng et al., 1995, J. Immunol. 154:5590- 5600; and ViI et al., 1992, PNAS 89:11337- 11341. The fusion of an antibody to a moiety does not necessarily need to be direct, but may occur through linker sequences. Such linker molecules are commonly known in the art and described in Denardo et al., 1998, Clin Cancer Res. 4:2483-90; Peterson et al., 1999, Bioconjug. Chem. 10:553; Zimmerman et al., 1999, Nucl. Med. Biol. 26:943-50; Garnett, 2002, Adv. Drug Deliv. Rev. 53:171-216, each of which is incorporated by reference herein in its entirety.

[00347] Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.

[00348] The prophylactic or therapeutic moiety or drug conjugated to an anti-

SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti- MGC15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti- NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti- PLVAP, anti-FLJ31528, anti-FLJ90709, anti-VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti- CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti- VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-0CIAD2, anti- PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ12443, anti- ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti~KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-F0LR2, anti-EMR2, ENTPDl, anti- ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ 14281, anti-FAM8Al, anti- TMED7, anti~C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti- FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti-ATP13Al, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti- GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibody of the invention should be chosen to achieve the desired prophylactic or therapeutic effect(s) for the treatment, management or prevention cancer. A clinician or other medical personnel should consider the following when deciding on which therapeutic moiety or drug to conjugate to an antibody that immunospecifically binds to an SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib polypeptide or fragment thereof: the nature of the disease, the severity of the disease, and the condition of the subject.

[00349] A conjugated agent's relative efficacy in comparison to the free agent can depend on a number of factors. For example, rate of uptake of the antibody-agent into the cell (e.g., by endocytosis), rate/efficiency of release of the agent from the antibody, rate of export of the agent from the cell, etc. can all effect the action of the agent. Antibodies used for targeted delivery of agents can be assayed for the ability to be endocytosed by the relevant cell type (i.e., the cell type associated with the disorder to be treated) by any method known in the art. Additionally, the type of linkage used to conjugate an agent to an antibody should be assayed by any method known in the art such that the agent action within the target cell is not impeded.

[00350] Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.

5.6.2.4 GENE THERAPY TECHNIQUES

[00351] Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described below.

[00352] In specific embodiments, SLC 12A2, FLJ23375, GRM5, TAS2R1 , NRXN2,

C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib antisense oligonucleotides, or the combination thereof are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof, by way of gene therapy. In other embodiments, nucleic acid molecules comprising nucleotide sequences encoding one or more anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti- C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti- GGTL3, anti-PL VAP, anti-FLJ31528, anti-FLJ90709, anti-VEZATIN, anti-TMPRSS9, anti- ATP13A5, anti-PKHDlLl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GKOOl, anti-0CIAD2, anti- PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti- ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-F0LR2, anti-EMR2, ENTPDl, anti- ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ 14281, anti-FAM8Al, anti- TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti- FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti-ATP13Al, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti- GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof, by way of gene therapy. In other embodiments, nucleic acid molecules comprising nucleotide sequences encoding SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib proteins or fragments thereof are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof, by way of gene therapy. In yet other embodiments, nucleic acid molecules comprising sequences encoding one or more dominant-negative SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NET02, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib polypeptides are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof, by way of gene therapy. In yet other embodiments, nucleic acid molecules comprising sequences encoding one or more soluble forms of SLC 12 A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA83O, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib polypeptides are administered to prevent, treat, manage or ameliorate cancer or a symptom thereof, by way of gene therapy.

[00353] For general reviews of the methods of gene therapy, see Goldspiel et al., 1993,

Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, 1993, Science 260:926-932; and Morgan and Anderson, 1993, Ann. Rev. Biochem. 62:191-217; May, 1993, TIBTECH 11(5): 155-215). Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), 1993, Current Protocols in Molecular Biology, John Wiley & Sons, NY; and Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY.

[00354] In one aspect, a composition of the invention comprises nucleic acid sequences encoding one or more anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti~FLJ90709, anti-VEZATIN, anti- TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl 8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti- TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti- GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orβ, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies or fragments thereof in a suitable host. In particular, such nucleic acid sequences have promoters operably linked to the anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti- TAS2R1, anti-NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti- KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl 8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti- BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti-GK001, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILIRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATP10B, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564D166, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and/or anti-UPK-lb antibodies or fragments thereof, said promoter being inducible or constitutive, and, optionally, tissue-specific. In a specific embodiment, a composition of the invention comprises nucleic acid sequences encoding one or more soluble forms of proteins [00355] In another aspect, a composition of the invention comprises nucleic acid sequences encoding dominant-negative SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14or£27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib polypeptides, said nucleic acid sequences being part of expression vectors that express dominant-negative SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib polypeptides in a suitable host. In particular, such nucleic acid sequences have promoters operably linked to the dominant-negative SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPRl 54, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib coding sequences, said promoter being inducible or constitutive, and, optionally, tissue-specific. In another particular embodiment, nucleic acid molecules are used in which the dominant-negative SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orβ, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the dominant-negative SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, Cl4orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib nucleic acids (Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435-438).

[00356] Delivery of the nucleic acids into a patient may be either direct, in which case the patient is directly exposed to the nucleic acid or nucleic acid-carrying vectors, or indirect, in which case, cells are first transformed with the nucleic acids in vitro, then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy.

[00357] In a specific embodiment, the nucleic acid sequence is directly administered in vivo, where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing it as part of an appropriate nucleic acid expression vector and administering it so that they become intracellular, e.g., by infection using defective or attenuated retro virals or other viral vectors (see U.S. Patent No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment {e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapsules, or by administering them in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432) (which can be used to target cell types specifically expressing the receptors), etc. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., International Publication Nos. WO 92/06180 dated April 16, 1992 (Wu et al.); WO 92/22635 dated December 23, 1992 (Wilson et al.); WO92/20316 dated November 26, 1992 (Findeis et al.); WO 93/14188 dated July 22, 1993 (Clarke et al.), WO 93/20221 dated October 14, 1993 (Young)). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435-438).

[00358] For example, a retroviral vector can be used. These retroviral vectors have been modified to delete retroviral sequences that are not necessary for packaging of the viral genome and integration into host cell DNA. The nucleic acid sequences encoding the proteins of interest (e.g., antibodies) to be used in gene therapy are cloned into one or more vectors, which facilitates delivery of the gene into a patient. More detail about retroviral vectors can be found in Boesen et al., 1994, Biotherapy 6:291-302, which describes the use of a retroviral vector to deliver the mdrl gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., 1994, J. Clin. Invest. 93:644-651; Kiem et al., 1994, Blood 83:1467-1473; Salmons and Gunzberg, 1993, Human Gene Therapy 4:129-141; and Grossman and Wilson, 1993, Curr. Opin. in Genetics and Devel. 3:110-114. [00359] Adenoviruses are other viral vectors that can be used in gene therapy.

Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, 1993, Current Opinion in Genetics and Development 3:499-503 present a review of adenovirus-based gene therapy. Bout et al., 1994, Human Gene Therapy 5:3-10 demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., 1991, Science 252:431-434; Rosenfeld et al., 1992, Cell 68:143-155; Mastrangeli et al., 1993, J. Clin. Invest 91:225-234; PCT Publication WO94/12649; and Wang, et al., 1995, Gene Therapy 2:775-783. In a preferred embodiment, adenovirus vectors are used.

[00360] Adeno-associated virus (AAV) has also been proposed for use in gene therapy

(Walsh et al., 1993, Proc. Soc. Exp. Biol. Med. 204:289-300; U.S. Patent No. 5,436,146). [00361] Another approach to gene therapy involves transferring a gene to cells in tissue culture by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene. Those cells are then delivered to a patient.

[00362] In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, 1993, Meth. Enzymol.

217:599-618; Cohen et al., 1993, Meth. Enzymol. 217:618-644; Cline, 1985, Pharmac. Ther.

29:69-92) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted.

The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny.

[00363] The resulting recombinant cells can be delivered to a patient by various methods known in the art. Recombinant prostate, ovary, lung, colon, pancreas or bladder cells are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art.

[00364] Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells

(e.g., prostate cells, ovary cells, lung cells, colon cells, pancreatic cells and/or bladder cells), endothelial cells, keratinocytes, chondrocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc.

[00365] In a preferred embodiment, the cell used for gene therapy is autologous to the patient.

[00366] In one embodiment in which recombinant cells are used in gene therapy, nucleic acid sequences encoding proteins of interest (e.g., antibodies) are introduced into the cells such that they are expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention

(see, e.g., International Publication No. WO 94/08598, dated April 28, 1994; Stemple and

Anderson, 1992, Cell 71:973-985; Rheinwald, 1980, Meth. Cell Bio. 21A:229; and Pittelkow and Scott, 1986, Mayo Clinic Proc. 61:771).

[00367] Promoters that may be used to control the expression of nucleic acid sequences encoding proteins of interest (e.g., antibodies) may be constitutive, inducible or tissue- specific. Non-limiting examples include the SV40 early promoter region (Bernoist and Chambon, 1981, Nature 290:304-310), the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto, et al., 1980, Cell 22:787-797), the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. USA 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster et al., 1982, Nature 296:39-42); prokaryotic expression vectors such as the β-lactamase promoter (Villa-Kamaroff et al., 1978, Proc. Natl. Acad. Sci. USA 75:3727-3731), or the tac promoter (DeBoer et al., 1983, Proc. Natl. Acad. Sci. USA 80:21-25); see also "Useful proteins from recombinant bacteria" in Scientific American, 1980, 242:74-94; plant expression vectors comprising the nopaline synthetase promoter region (Herrera-Estrella et al., Nature 303:209-213) or the cauliflower mosaic virus 35S RNA promoter (Gardner et al., 1981, Nucl. Acids Res. 9:2871), and the promoter of the photosynthetic enzyme ribulose biphosphate carboxylase (Herrera-Estrella et al., 1984, Nature 310:115-120); promoter elements from yeast or other fungi such as the Gal 4 promoter, the ADC (alcohol dehydrogenase) promoter, PGK (phosphoglycerol kinase) promoter, alkaline phosphatase promoter, and the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells (Swift et al., 1984, Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant. Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); insulin gene control region which is active in pancreatic beta cells (Hanahan, 1985, Nature 315:115-122), immunoglobulin gene control region which is active in lymphoid cells (Grosschedl et al.,

1984, Cell 38:647-658; Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, MoI. Cell. Biol. 7:1436-1444), mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells (Leder et al., 1986, Cell 45:485-495), albumin gene control region which is active in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276), alpha-fetoprotein gene control region which is active in liver (Krumlauf et al.,

1985, MoI. Cell. Biol. 5:1639-1648; Hammer et al., 1987, Science 235:53-58; alpha

1 -antitrypsin gene control region which is active in the liver (Kelsey et al., 1987, Genes and Devel. 1:161-171), beta-globin gene control region which is active in myeloid cells (Mogram et al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94; myelin basic protein gene control region which is active in oligodendrocyte cells in the brain (Readhead et al., 1987, Cell 48:703-712); myosin light chain-2 gene control region which is active in skeletal muscle (Sani, 1985, Nature 314:283-286), and gonadotropic releasing hormone gene control region which is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378). [00368] In a specific embodiment, the nucleic acid to be introduced for purposes of gene therapy comprises an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by controlling the presence or absence of the appropriate inducer of transcription.

5.6.3 OTHERPROPHYLACTICAND THERAPEUTICAGENTS

[00369] The invention provides methods for treating, managing, preventing and/or ameliorating cancer by administering one or more compounds identified by the methods of the invention in combination with one or more therapies. Preferably, those other therapies are currently being used or are useful in the treatment, management or prevention of cancer or symptoms thereof. In a specific embodiment, the invention provides a method of treating, managing, preventing and/or ameliorating cancer or a symptom thereof, the method comprising administering to a subject in need thereof an effective amount of a compound identified by the methods of the invention and an effective amount of a therapy other than a compound identified by the methods of the invention. Any therapy (e.g., prophylactic or therapeutic agents) which is known to be useful, or which has been used or is currently being used for the prevention, management, treatment or amelioration of cancer or a symptom thereof can be used in combination with compound identified by the methods of the invention in accordance with the invention described herein. In a specific embodiment, the invention provides a method of treating, managing, preventing and/or ameliorating cancer or a symptom thereof, the method comprising administering to a subject in need thereof an effective amount of a compound identified by the methods of the invention and an effective amount one or more other therapies, including but not limited to, chemotherapy, biological therapy, immunotherapy, radiation therapy, and surgery. See, e.g., Gilman et al., Goodman and Gilman' s : The Pharmacological Basis of Therapeutics, Tenth Ed., McGraw-Hill, New York, 2001; The Merck Manual of Diagnosis and Therapy, Berkow, M.D. et al. (eds.), 17th Ed., Merck Sharp & Dohme Research Laboratories, Rahway, NJ, 1999; and Cecil Textbook of Medicine, 20th Ed., Bennett and Plum (eds.), W.B. Saunders, Philadelphia, 1996, for information regarding therapies, in particular prophylactic or therapeutic agents, which have been or are currently being used for preventing, treating, managing, and/or ameliorating a cancer or a symptom thereof. Therapeutic or prophylactic agents include, but are not limited to, small molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids, (e.g., DNA and RNA nucleotides including, but not limited to, antisense nucleotide sequences, triple helices, RNAi, and nucleotide sequences encoding biologically active proteins, polypeptides or peptides) antibodies, synthetic or natural inorganic molecules, mimetic agents, and synthetic or natural organic molecules. Examples of prophylactic and therapeutic agents include, but are not limited to, immunomodulatory agents, anti-angiogenic agents, TNF-α antagonists, anti-inflammatory agents {e.g., adrenocorticoids, corticosteroids, {e.g., beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone, methylprednisolone, prednisolone, prednisone, hydrocortisone), glucocorticoids, steroids, and non-steroidal antiinflammatory drugs {e.g., aspirin, ibuprofen, diclofenac, and COX-2 inhibitors), anticholinergic agents {e.g., ipratropium bromide and oxitropium bromide), sulphasalazine, penicillamine, dapsone, antihistamines, anti-malarial agents {e.g., hydroxychloroquine), antiviral agents, and antibiotics {e.g., dactinomycin (formerly actinomycin), bleomycin, erythromycin, penicillin, mithramycin, and anthramycin (AMC)), anti-cancer therapies, antiviral agents, anti-bacterial agents, and anti-fungal agents.

[00370] In one embodiment, a compound identified by the methods of the invention is administered to a subject in need thereof in combination with a therapy currently used or known to treat, manage, prevent and/or ameliorate cancer or a symptom thereof. In another embodiment, a compound identified by the methods of the invention is administered to a subject in need thereof in combination with an immunomodulatory agent. In another embodiment, compound of the invention is administered to a subject in need thereof in combination with an anti-angiogenic agent. In another embodiment, an compound of the invention is administered to a subject in need thereof in combination with a TNF-α antagonist. In yet another embodiment, a compound identified by the methods of the invention is administered to a subject in need thereof in combination with an anti-cancer agent.

[00371] The therapies can be administered to a subject in need thereof sequentially or concurrently. In particular, the therapies should be administered to a subject at exactly the same time or in a sequence within a time interval such that the therapies can act together to provide an increased benefit than if they were administered otherwise. In a specific embodiment, the combination therapies of the invention comprise an effective amount of one or more compounds identified by the methods of the invention and an effective amount of at least one other therapy which has the same mechanism of action as said compounds identified by the methods of the invention. In a specific embodiment, the combination therapies of the invention comprise an effective amount of one or more compounds identified by the methods of the invention and an effective amount of at least one other therapy {e.g., prophylactic or therapeutic agent) which has a different mechanism of action than said compound identified by the methods of the invention. In certain embodiments, the combination therapies of the present invention improve the prophylactic or therapeutic effect of one or more compounds identified by the methods of the invention by functioning together with the compounds identified by the methods of the invention to have an additive or synergistic effect. In certain embodiments, the combination therapies of the present invention reduce the side effects associated with the prophylactic or therapeutic agents. In various embodiments, the therapies are administered to a patient less than 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, a about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In preferred embodiments, two or more therapies are administered within the same patient visit.

[00372] The prophylactic or therapeutic agents of the combination therapies can be administered to a subject, preferably a human subject, in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.

[00373] In a specific embodiment, a pharmaceutical composition comprising one or more compounds identified by the methods of the invention described herein is administered to a subject, preferably a human, to prevent, treat, manage and/or ameliorate cancer. In accordance with the invention, pharmaceutical compositions of the invention may also comprise one or more therapies (e.g., prophylactic or therapeutic agents), other than the compounds identified by the methods of the invention. Preferably, such other therapies are currently being used, have been used, or are known to be useful in the prevention, treatment or amelioration of one or more symptoms associated with cancer.

5.6.3.1 IMMUNOMODULATORY AGENTS

[00374] In certain embodiments, the present invention provides compositions comprising one or more compounds identified by the methods of the invention and one or more immunomodulatory agents (i.e., agents which modulate the immune response in a subject), and methods for treating, managing, preventing or ameliorating cancer or a symptom thereof, in a subject comprising the administration of said compositions. The invention also provides methods for treating, managing, preventing or ameliorating cancer or a symptom thereof comprising the administration of a compound identified by the methods in combination with one or more immunomodulatory agents. In a specific embodiment of the invention, the immunomodulatory agent inhibits or suppresses the immune response in a human subject. Immunomodulatory agents are well-known to one skilled in the art and can be used in the methods and compositions of the invention.

[00375] Any immunomodulatory agent well-known to one of skill in the art may be used in the methods and compositions of the invention. Immunomodulatory agents can affect one or more or all aspects of the immune response in a subject. Aspects of the immune response include, but are not limited to, the inflammatory response, the complement cascade, leukocyte and lymphocyte differentiation, proliferation, and/or effector function, monocyte and/or basophil counts, and the cellular communication among cells of the immune system. In certain embodiments of the invention, an immunomodulatory agent modulates one aspect of the immune response. In other embodiments, an immunomodulatory agent modulates more than one aspect of the immune response. In a preferred embodiment of the invention, the administration of an immunomodulatory agent to a subject inhibits or reduces one or more aspects of the subject's immune response capabilities. In a specific embodiment of the invention, the immunomodulatory agent inhibits or suppresses the immune response in a subject.

[00376] In accordance with the invention, an immunomodulatory agent is not antibody that immunospecifically binds to a SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, CHorflόO, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib polypeptide. In certain embodiments, an immunomodulatory agent is not an anti-angiogenic agent. In certain embodiments, an immunomodulatory agent is not an antiinflammatory agent. In other emobidments, an immunomodulatory agent is not a TNF-α antagonist. In certain embodiments, an immunomodulatory agent is not an anti-cancer agent. [00377] Examples of immunomodulatory agents include, but are not limited to, proteinaceous agents such as cytokines, peptide mimetics, and antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab')₂ fragments or epitope binding fragments), nucleic acid molecules (e.g., antisense nucleic acid molecules and triple helices), small molecules, organic compounds, and inorganic compounds. In particular, immunomodulatory agents include, but are not limited to, methotrexate, leflunomide, cyclophosphamide, Cytoxan, Immuran, cyclosporine A, minocycline, azathioprine, antibiotics (e.g., FK506 (tacrolimus)), methylprednisolone (MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin, brequinar, malononitriloamindes (e.g., leflunamide), T cell receptor modulators, cytokine receptor modulators, and modulators mast cell modulators. [00378] Examples of T cell receptor modulators include, but are not limited to, anti-T cell receptor antibodies (e.g., anti-CD4 antibodies (e.g., cM-T412 (Boeringer), IDEC-CE9.1® (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (e.g., Nuvion (Product Design Labs), OKT3 (Johnson & Johnson), or Rituxan (IDEC)), anti-CD5 antibodies (e.g., an anti-CD5 ricin-linked immunoconjugate), anti-CD7 antibodies (e.g., CHH-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand monoclonal antibodies (e.g., IDEC-131 (IDEC)), anti-CD52 antibodies (e.g., CAMPATH IH (Ilex)), anti- CD2 antibodies (e.g., siplizumab (Medlmmune, Inc., International Publication Nos. WO 02/098370 and WO 02/069904)), anti-CDl Ia antibodies (e.g., Xanelim (Genentech)), and anti-B7 antibodies (e.g., IDEC-114) (IDEC))), CTLA4-immunoglobulin, and LFA-3TIP (Biogen, International Publication No. WO 93/08656 and U.S. Patent No. 6,162,432). [00379] Examples of cytokine receptor modulators include, but are not limited to, soluble cytokine receptors (e.g., the extracellular domain of a TNF -y receptor or a fragment thereof, the extracellular domain of an IL-Iy receptor or a fragment thereof, and the extracellular domain of an IL-6 receptor or a fragment thereof), cytokines or fragments thereof (e.g., interleukin IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-IO, IL-11, IL-12, IL- 13, IL- 15, IL-23, TNF-α, TNF-γ, interferon (IFN)-α, IFN-γ, IFN-β, and GM-CSF), anti- cytokine receptor antibodies (e.g., anti-IFN receptor antibodies, anti-IL-2 receptor antibodies (e.g., Zenapax (Protein Design Labs)), anti-IL-3 receptor antibodies, anti-IL-4 receptor antibodies, anti-IL-6 receptor antibodies, anti-IL-10 receptor antibodies, anti-IL-12 receptor antibodies, anti-IL-13 receptor antibodies, anti-IL-15 receptor antibodies, and anti-IL-23 receptor antibodies), anti-cytokine antibodies (e.g. , anti-IFN antibodies, anti-TNF-α antibodies, anti-IL-lβ antibodies, anti-IL-3 antibodies, anti-IL-6 antibodies, anti-IL-8 antibodies (e.g., ABX-IL-8 (Abgenix)), anti-IL-12 antibodies, anti-IL-13 antibodies, anti-IL- 15 antibodies, and anti-IL-23 antibodies).

[00380] In a specific embodiment, a cytokine receptor modulator is IL-3, IL-4, IL-10, or a fragment thereof. In another embodiment, a cytokine receptor modulator is an anti-IL-ly antibody, anti-IL-6 antibody, anti-IL-12 receptor antibody, or anti-TNF-α antibody. In another embodiment, a cytokine receptor modulator is the extracellular domain of a TNF-α receptor or a fragment thereof. In certain embodiments, a cytokine receptor modulator is not a TNF-α antagonist.

[00381] An immunomodulatory agent may be selected to interfere with the interactions between the T helper subsets (THl or TH2) and B cells to inhibit neutralizing antibody formation. Antibodies that interfere with or block the interactions necessary for the activation of B cells by TH (T helper) cells, and thus block the production of neutralizing antibodies, are useful as immunomodulatory agents in the methods of the invention. For example, B cell activation by T cells requires certain interactions to occur (Durie et al, Immunol. Today, 15(9):406-410 (1994)), such as the binding of CD40 ligand on the T helper cell to the CD40 antigen on the B cell, and the binding of the CD28 and/or CTLA4 ligands on the T cell to the B7 antigen on the B cell. Without both interactions, the B cell cannot be activated to induce production of the neutralizing antibody.

[00382] The CD40 ligand (CD40L)-CD40 interaction is a desirable point to block the immune response because of its broad activity in both T helper cell activation and function as well as the absence of redundancy in its signaling pathway. Thus, in a specific embodiment of the invention, the interaction of CD40L with CD40 is transiently blocked at the time of administration of one or more of the immunomodulatory agents. This can be accomplished by treating with an agent which blocks the CD40 ligand on the TH cell and interferes with the normal binding of CD40 ligand on the T helper cell with the CD40 antigen on the B cell. An antibody to CD40 ligand (anti-CD40L) (available from Bristol-Myers Squibb Co; see, e.g., European patent application 555,880, published Aug. 18, 1993) or a soluble CD40 molecule can be selected and used as an immunomodulatory agent in accordance with the methods of the invention.

[00383] An immunomodulatory agent may be selected to inhibit the interaction between THl cells and cytotoxic T lymphocytes ("CTLs") to reduce the occurrence of CTL- mediated killing. An immunomodulatory agent may be selected to alter (e.g., inhibit or suppress) the proliferation, differentiation, activity and/or function of the CD4+ and/or CD8+ T cells. For example, antibodies specific for T cells can be used as immunomodulatory agents to deplete, or alter the proliferation, differentiation, activity and/or function of CD4+ and/or CD8+ T cells.

[00384] In another embodiment, an immunomodulatory agent which reduces or inhibits one or more biological activities (e.g., the differentiation, proliferation, and/or effector functions) of THO, THl, and/or TH2 subsets of CD4+ T helper cells is administered to a subject at risk of or with cancer in accordance with the methods of the invention. One example of such an immunomodulatory agent is IL-4. IL-4 enhances antigen-specific activity of TH2 cells at the expense of the THl cell function (see, e.g., Yokota et al, 1986 Proc. Natl. Acad. ScL, USA, 83:5894-5898; and U.S. Pat. No. 5,017,691). Other examples of immunomodulatory agents that affect the biological activity (e.g., proliferation, differentiation, and/or effector functions) of T-helper cells (in particular, THl and/or TH2 cells) include, but are not limited to, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-15, IL-23, and interferon (IFN)-γ.

[00385] In another embodiment, an immunomodulatory agent administered to a subject at risk of or with cancer in accordance with the methods of the invention is a cytokine that prevents antigen presentation. In a specific embodiment, an immunomodulatory agent used in the methods of the invention is IL-10. IL-10 also reduces or inhibits macrophage action which involves bacterial elimination.

[00386] An immunomodulatory agent may be selected to reduce or inhibit the activation, degranulation, proliferation, and/or infiltration of mast cells. In certain embodiments, the immunomodulatory agent interferes with the interactions between mast cells and mast cell activating agents, including, but not limited to stem cell factors (c-kit ligands), IgE, IL-4, environmental irritants, and infectious agents. In a specific embodiment, the immunomodulatory agent reduces or inhibits the response of mast cells to environmental irritants such as, but not limited to pollen, dust mites, tobacco smoke, and/or pet dander. In another specific embodiment, the immunomodulatory agent reduces or inhibits the response of mast cells to infectious agents, such as viruses, bacteria, and fungi. Examples of mast cell modulators that reduce or inhibit the activation, degranulation, proliferation, and/or infiltration of mast cells include, but are not limited to, stem cell factor (c-kit receptor ligand) inhibitors (e.g., mAb 7H6, mAb 8H7a, and pAb 1337 (see Mendiaz et al., 1996, Eur J Biochem 293(3):842-849), FK506 and CsA (Ito et al., 1999 Arch Dermatol Res 291(5):275- 283), dexamthasone and fluconcinonide (see Finooto et al., 1997, J. Clin. Invest. 99(7): 1721- 1728)), c-kit receptor inhibitors (e.g., STI 571 (formerly known as CGP 57148B) (see Heinrich et al., 2000 Blood 96(3):925-932)), mast cell protease inhibitors (e.g., GW-45 and GW-58 (see, Temkin et al., 2002, J Immunol 169(5):2662-2669), wortmannin, LY 294002, calphostin C,and cytochalasin D (see Vosseller et al., 1997, MoI Biol Cell 1997:909-922), genistein, KT5926, and staurosproine (see Nagai et al. 1995, Biochem Biophys Res Commun 208(2):576-581), and lactoferrin (see He et al., 2003 Biochem Pharmacol 65(6):1007-1015)), relaxin ("RLX") (see Bani et al., 2002 Int Immunopharmacol 2(8): 1195-1294), ), IgE antagonists (e.g., antibodies rhuMAb-E25 omalizumab (see Finn et al., 2003 J Allergy Clin Immuno 111(2):278-284; Corren et al., 2003 J Allergy Clin Irnmuno 11 l(l):87-90; Busse and Neaville, 2001 Curr Opin Allergy Clin Immunol. l(l):105-108; and Tang and Powell, 2001, Eur J Pediatr 160(12): 696-704), HMK-12 and 6HD5 (see Miyajima et al., 2202 Int Arch Allergy Immuno 128(l):24-32), and mAB Hu-901 (see van Neerven et al., 2001 Int Arch Allergy Immuno 124(l-3):400), IL-3 antagonist, IL-4 antagonists, IL-10 antagonists, and TGF-beta (see Metcalfe et al., 1995, Exp Dermatol 4(4 Pt 2):227-230). [00387] In a preferred embodiment, proteins, polypeptides or peptides (including antibodies) that are utilized as immunomodulatory agents are derived from the same species as the recipient of the proteins, polypeptides or peptides so as to reduce the likelihood of an immune response to those proteins, polypeptides or peptides. In another preferred embodiment, when the subject is a human, the proteins, polypeptides, or peptides that are utilized as immunomodulatory agents are human or humanized.

[00388] In accordance with the invention, one or more immunomodulatory agents are administered to a subject at risk of or with cancer prior to, subsequent to, or concomitantly with one or more compounds identified by the methods of the invention. Preferably, one or more immunomodulatory agents are administered in combination with one or more compounds identified by the methods of the invention to a subject at risk of or with cancer to reduce or inhibit one or more aspects of the immune response as deemed necessary by one of skill in the art. Any technique well-known to one skilled in the art can be used to measure one or more aspects of the immune response in a particular subject, and thereby determine when it is necessary to administer an immunomodulatory agent to said subject. In a preferred embodiment, a mean absolute lymphocyte count of approximately 500 cells/mm³, preferably 600 cells/ mm³, 650 cells/ mm³, 700 cells/ mm³, 750 cells/ mm³, 800 cells/ mm³, 900 cells/ mm³, 1000 cells/ mm³, 1100 cells/ mm³, or 1200 cells/ mm³ is maintained in a subject. In another preferred embodiment, a subject at risk of or with cancer is not administered an immunomodulatory agent if their absolute lymphocyte count is 500 cells/ mm³ or less, 550 cells/ mm³ or less, 600 cells/ mm³ or less, 650 cells/ mm³ or less, 700 cells/ mm³ or less, 750 cells/ mm³ or less, or 800 cells/ mm³ or less.

[00389] In a preferred embodiment, one or more immunomodulatory agents are administered in combination with one or more compounds identified by the methods of the invention to a subject at risk of or with cancer so as to transiently reduce or inhibit one or more aspects of the immune response. Such a transient inhibition or reduction of one or more aspects of the immune system can last for hours, days, weeks, or months. Preferably, the transient inhibition or reduction in one or more aspects of the immune response lasts for a few hours (e.g., 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours, 18 hours, 24 hours, 36 hours, or 48 hours), a few days (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, or 14 days), or a few weeks (e.g., 3 weeks, 4 weeks, 5 weeks or 6 weeks). The transient reduction or inhibition of one or more aspects of the immune response enhances the prophylactic and/or therapeutic effect(s) of a compound identified by the methods of the invention. [00390] Nucleic acid molecules encoding proteins, polypeptides, or peptides with immunomodulatory activity or proteins, polypeptides, or peptides with immunomodulatory activity can be administered to a subject at risk of or with cancer in accordance with the methods of the invention. Further, nucleic acid molecules encoding derivatives, analogs, or fragments of proteins, polypeptides, or peptides with immunomodulatory activity, or derivatives, analogs, or fragments of proteins, polypeptides, or peptides with immunomodulatory activity can be administered to a subject at risk of or with cancer in accordance with the methods of the invention. Preferably, such derivatives, analogs, and fragments retain the immunomodulatory activity of the full-length, wild-type protein, polypeptide, or peptide.

[00391] The immunomodulator activity of an immunomodulatory agent can be determined in vitro and/or in vivo by any technique well-known to one skilled in the art, including, e.g., by CTL assays, proliferation assays, immunoassays (e.g. ELISAs) for the expression of particular proteins such as co-stimulatory molecules and cytokines, and FACS.

5.6.3.2 ANTI-INFLAMMATORY THERAPIES

[00392] In certain embodiments, the present invention provides compositions comprising one or more compounds of the invention and one or more anti-inflammatory agents, and methods for treating, managing, preventing or ameliorating cancer in a subject comprising the administration of said compositions. Any anti-inflammatory agent, including agents useful in therapies for inflammatory disorders, well-known to one of skill in the art can be used in the compositions and methods of the invention. Non-limiting examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs, anticholinergics (e.g., atropine sulfate, atropine methylnitrate, and ipratropium bromide (ATRO VENT™)), beta2-agonists (e.g., abuterol (VENTOLIN™ and PROVENTIL™), bitolterol (TORNALATE™), levalbuterol (XOPONEX™), metaproterenol (ALUPENT™), pirbuterol (MAXAIR™), terbutlaine (BRETHAIRE™ and BRETHINE™), albuterol (PROVENTIL™, REPETABS™, and VOLMAX™), formoterol (FORADIL AEROLIZER™), and salmeterol (SEREVENT™ and SEREVENT DISKUS™)), and methylxanthines (e.g., theophylline (UNIPHYL™, THEO-DUR™, SLO-BID™, AND TEHO-42™)). Examples of NSAIDs include, but are not limited to, aspirin, ibuprofen, celecoxib (CELEBREX™), diclofenac (VOLTAREN™), etodolac (LODINE™), fenoprofen (NALFON™), indomethacin (INDOCIN™), ketoralac (TORADOL™), oxaprozin (DAYPRO™), nabumentone (RELAFEN™), sulindac (CLINORIL™), tolmentin (TOLECTIN™), rofecoxib (V IOX™), naproxen (ALEVE™, NAPROSYN™), ketoprofen (ACTRON™) and nabumetone (RELAFEN™). Such NSAIDs function by inhibiting a cyclooxgenase enzyme (e.g., COX-I and/or COX-2). Examples of steroidal anti- inflammatory drugs include, but are not limited to, glucocorticoids, dexamethasone (DECADRON™), corticosteroids (e.g., methylprednisolone (MEDROL™)), cortisone, hydrocortisone, prednisone (PREDNISONE™ and DELTASONE™), prednisolone (PRELONE™ and PEDIAPRED™), triamcinolone, azulfidine, and inhibitors of eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes).

[00393] Anti-inflammatory therapies and their dosages, routes of administration, and recommended usage are known in the art and have been described in such literature as the Physician 's Desk Reference (59th ed., 2005).

5.6.3.3 ANTI-ANGIOGENIC THERAPIES

[00394] In certain embodiments, the present invention provides compositions comprising one or more compounds of the invention and one or more anti-angiogenic agents, and methods for treating, managing, preventing or ameliorating cancer in a subject comprising the administration of said compositions. Any anti-angiogenic agent well-known to one of skill in the art can be used in the compositions and methods of the invention. [00395] Any anti-angiogenic agent well-known to one of skill in the art can be used in the compositions and methods of the invention. Non-limiting examples of anti-angiogenic agents include proteins, polypeptides, peptides, fusion proteins, antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab fragments, F(ab)2 fragments, and antigen-binding fragments thereof) such as antibodies that immunospecifically bind to TNF-α, nucleic acid molecules (e.g., antisense molecules or triple helices), organic molecules, inorganic molecules, and small molecules that reduce or inhibit angiogenesis. In particular, examples of anti-angiogenic agents, include, but are not limited to, endostatin, angiostatin, apomigren, anti-angiogenic antithrombin III, the 29 kDa N-terminal and a 40 kDa C-terminal proteolytic fragments of fibronectin, a uPA receptor antagonist, the 16 kDa proteolytic fragment of prolactin, the 7.8 kDa proteolytic fragment of platelet factor-4, the anti-angiogenic 24 amino acid fragment of platelet factor-4, the anti-angiogenic factor designated 13.40, the anti-angiogenic 22 amino acid peptide fragment of thrombospondin I, the anti-angiogenic 20 amino acid peptide fragment of SPARC, RGD and NGR containing peptides, the small anti-angiogenic peptides of laminin, fibronectin, procollagen and EGF, integrin αvβ3 antagonists, acid fibroblast growth factor (aFGF) antagonists, basic fibroblast growth factor (bFGF) antagonists, vascular endothelial growth factor (VEGF) antagonists (e.g., anti-VEGF antibodies (e.g., AVASTIN™ (Genentech)),VEGF receptor (VEGFR) antagonists (e.g., anti- VEGFR antibodies) and anti-integrin antagonists (e.g., REOPRO® (abciximab) (Centocor) which binds to the glycoprotein Ilb/IIIa receptor on the platelets for the prevention of clot formation).

[00396] Examples of integrin αvβ3 antagonists include, but are not limited to, proteinaceous agents such as non-catalytic metalloproteinase fragments, RGD peptides, peptide mimetics, fusion proteins, disintegrins or derivatives or analogs thereof, and antibodies that immunospecifically bind to integrin αvβ3, nucleic acid molecules, organic molecules, and inorganic molecules. Non-limiting examples of antibodies that immunospecifically bind to integrin αvβ3 include 11D2 (Searle), LM609 (Scripps), and VITAXIN™ (Medlmmune, Inc.). Non-limiting examples of small molecule peptidometric integrin αvβ3 antagonists include S836 (Searle) and S448 (Searle). Examples of disintegrins include, but are not limited to, Accutin. The invention also encompasses the use of any of the integrin αvβ3 antagonists disclosed in the following U.S. Patents and International publications in the compositions and methods of the invention: U.S. Patent Nos. 5,149,780; 5,196,511; 5,204,445; 5,262,520; 5,306,620; 5,478,725; 5,498,694; 5,523,209; 5,578,704; 5,589,570; 5,652,109; 5,652,110; 5,693,612; 5,705,481; 5,753,230; 5,767,071; 5,770,565; 5,780,426; 5,817,457; 5,830,678; 5,849,692; 5,955,572; 5,985,278; 6,048,861; 6,090,944; 6,096,707; 6,130,231; 6,153,628; 6,160,099; and 6,171,588; and International Publication Nos. WO 95/22543; WO 98/33919; WO 00/78815; and WO 02/070007, each of which is incorporated herein by reference in its entirety.

[00397] In a specific embodiment of the invention, an anti-angiogenic agent is endostatin. Naturally occurring endostatin consists of the C-terminal -180 amino acids of collagen XVIII (cDNAs encoding two splice forms of collagen XVIII have GenBank Accession Nos. AF18081 and AF18082). In another embodiment of the invention, an anti- angiogenic agent is a plasminogen fragment (the coding sequence for plasminogen can be found in GenBank Accession Nos. NM_000301 and A33096). Angiostatin peptides naturally include the four kringle domains of plasminogen, kringle 1 through kringle 4. It has been demonstrated that recombinant kringle 1, 2 and 3 possess the anti-angiogenic properties of the native peptide, whereas kringle 4 has no such activity (Cao et al., 1996, J. Biol. Chem. 271 :29461-29467). Accordingly, the angiostatin peptides comprises at least one and preferably more than one kringle domain selected from the group consisting of kringle 1, kringle 2 and kringle 3. In a specific embodiment, the anti-angiogenic peptide is the 40 kDa isoform of the human angiostatin molecule, the 42 kDa isoform of the human angiostatin molecule, the 45 kDa isoform of the human angiostatin molecule, or a combination thereof. In another embodiment, an anti-angiogenic agent is the kringle 5 domain of plasminogen, which is a more potent inhibitor of angiogenesis than angiostatin (angiostatin comprises kringle domains 1-4). In another embodiment of the invention, an anti-angiogenic agent is antithrombin III. Antithrombin III, which is referred to hereinafter as antithrombin, comprises a heparin binding domain that tethers the protein to the vasculature walls, and an active site loop which interacts with thrombin. When antithrombin is tethered to heparin, the protein elicits a conformational change that allows the active loop to interact with thrombin, resulting in the proteolytic cleavage of said loop by thrombin. The proteolytic cleavage event results in another change of conformation of antithrombin, which (i) alters the interaction interface between thrombin and antithrombin and (ii) releases the complex from heparin (Carrell, 1999, Science 285:1861-1862, and references therein). O'Reilly et al. (1999, Science 285:1926-1928) have discovered that the cleaved antithrombin has potent anti- angiogenic activity. Accordingly, in one embodiment, an anti-angiogenic agent is the anti- angiogenic form of antithrombin. In another embodiment of the invention, an anti- angiogenic agent is the 40 IcDa and/or 29 kDa proteolytic fragment of fibronectin. [00398] In another embodiment of the invention, an anti-angiogenic agent is a urokinase plasminogen activator (uPA) receptor antagonist. In one mode of the embodiment, the antagonist is a dominant negative mutant of uPA (see, e.g., Crowley et al., 1993, Proc. Natl. Acad. Sci. USA 90:5021-5025). In another mode of the embodiment, the antagonist is a peptide antagonist or a fusion protein thereof (Goodson et al, 1994, Proc. Natl. Acad. Sci. USA 91:7129-7133). In yet another mode of the embodiment, the antagonist is a dominant negative soluble uPA receptor (Min et al., 1996, Cancer Res. 56:2428-2433). In another embodiment of the invention, a therapeutic molecule of the invention is the 16 kDaN- terminal fragment of prolactin, comprising approximately 120 amino acids, or a biologically active fragment thereof (the coding sequence for prolactin can be found in GenBank Accession No. NM_000948). In another embodiment of the invention, an anti-angiogenic agent is the 7.8 kDa platelet factor-4 fragment. In another embodiment of the invention, a therapeutic molecule of the invention is a small peptide corresponding to the anti-angiogenic 13 amino acid fragment of platelet factor-4, the anti-angiogenic factor designated 13.40, the anti-angiogenic 22 amino acid peptide fragment of thrombospondin I , the anti-angiogenic 20 amino acid peptide fragment of SPARC, the small anti-angiogenic peptides of laminin, fibronectin, procollagen, or EGF, or small peptide antagonists of integrin αvβ3 or the VEGF receptor. In another embodiment, the small peptide comprises an RGD or NGR motif. In certain embodiments, an anti-angiogenic agent is a TNF-α antagonist. In other embodiments, an anti-angiogenic agent is not a TNF- α antagonist.

[00399] Nucleic acid molecules encoding proteins, polypeptides, or peptides with anti- angiogenic activity, or proteins, polypeptides or peptides with anti-angiogenic activity can be administered to a subject at risk of or with cancer in accordance with the methods of the invention. Further, nucleic acid molecules encoding derivatives, analogs, fragments, or variants of proteins, polypeptides, or peptides with anti-angiogenic activity, or derivatives, analogs, fragments, or variants of proteins, polypeptides, or peptides with anti-angiogenic activity can be administered to a subject at risk of or with cancer in accordance with the methods of the invention. Preferably, such derivatives, analogs, variants, and fragments retain the anti-angiogenic activity of the full-length, wild-type protein, polypeptide, or peptide.

[00400] Proteins, polypeptides, or peptides that can be used as anti-angiogenic agents can be produced by any technique well-known in the art or described herein. Proteins, polypeptides or peptides with anti-angiogenic activity can be engineered so as to increase the in vivo half-life of such proteins, polypeptides, or peptides utilizing techniques well-known in the art or described herein. Preferably, anti-angiogenic agents that are commercially available are used in the compositions and methods of the invention. The anti-angiogenic activity of an agent can be determined in vitro and/or in vivo by any technique well-known to one skilled in the art.

5.6.3.4 TNF-α ANTAGONISTS

[00401] Any TNF-α antagonist well-known to one of skill in the art can be used in the compositions and methods of the invention. Non-limiting examples of TNF- α antagonists include proteins, polypeptides, peptides, fusion proteins, antibodies {e.g. , human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab fragments, F(ab)₂ fragments, and antigen- binding fragments thereof) such as antibodies that immunospecifically bind to TNF-y, nucleic acid molecules (e.g., antisense molecules or triple helices), organic molecules, inorganic molecules, and small molecules that blocks, reduces, inhibits or neutralizes a function, an activity and/or expression of TNF- α. In various embodiments, a TNF- α antagonist reduces the function, activity and/or expression of TNF-y by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% relative to a control such as phosphate buffered saline (PBS). [00402] Examples of antibodies that immunospecifically bind to TNF- α include, but are not limited to, infliximab (REMICADE®; Centacor), D2E7 (Abbott Laboratories/Knoll Pharmaceuticals Co., Mt. Olive, NJ.), CDP571 which is also known as HUMICADE™ and CDP-870 (both of Celltech/Pharmacia, Slough, U.K.), and TN3-19.12 (Williams et al., 1994, Proc. Natl. Acad. Sci. USA 91: 2762-2766; Thorbecke et al., 1992, Proc. Natl. Acad. Sci. USA 89:7375-7379). The present invention also encompasses the use of antibodies that immunospecifically bind to TNF-α disclosed in the following U.S. Patents in the compositions and methods of the invention: 5,136,021; 5,147,638; 5,223,395; 5,231,024; 5,334,380; 5,360,716; 5,426,181; 5,436,154; 5,610,279; 5,644,034; 5,656,272; 5,658,746; 5,698,195; 5,736,138; 5,741,488; 5,808,029; 5,919,452; 5,958,412; 5,959,087; 5,968,741; 5,994,510; 6,036,978; 6,114,517; and 6,171,787; each of which are herein incorporated by reference in their entirety. Examples of soluble TNF-α receptors include, but are not limited to, sTNF-Rl (Amgen), etanercept (ENBREL™; Immunex) and its rat homolog RENBREL™, soluble inhibitors of TNF- α derived from TNFrI, TNFrII (Kohno et al., 1990, Proc. Natl. Acad. Sci. USA 87:8331-8335), and TNF-α Inh (Seckinger et al, 1990, Proc. Natl. Acad. Sci. USA 87:5188-5192).

[00403] In one embodiment, a TNF-α antagonist used in the compositions and methods of the invention is a soluble TNF-α receptor. In a specific embodiment, a TNF-α antagonist used in the compositions and methods of the invention is etanercept (ENBREL™; Immunex) or a fragment, derivative or analog thereof. In another embodiment, a TNF-α antagonist used in the compositions and methods of the invention is an antibody that immunospecifically binds to TNF-α. In a specific embodiment, a TNF-α antagonist used in the compositions and methods of the invention is infliximab (REMIC ADE®; Centacor) a derivative, analog or antigen-binding fragment thereof.

[00404] Other TNF- α antagonists encompassed by the invention include, but are not limited to, IL-10, which is known to block TNF-α production via interferon y-activated macrophages (Oswald et al. 1992, Proc. Natl. Acad. Sci. USA 89:8676-8680), TNFR-IgG (Ashkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88:10535-10539), the murine product TBP-I (Serono/Yeda), the vaccine CytoTAb (Protherics), antisense molecule 104838 (ISIS), the peptide RDP-58 (SangStat), thalidomide (Celgene), CDC-801 (Celgene), DPC-333 (Dupont), VX-745 (Vertex), AGIX-4207 (AtheroGenics), ITF-2357 (Italfarmaco), NPI- 13021-31 (Nereus), SCIO-469 (Scios), TACE targeter (Immunix/AHP), CLX-120500 (Calyx), Thiazolopyrim (Dynavax), auranofϊn (Ridaura) (SmithKline Beecham Pharmaceuticals), quinacrine (mepacrine dichlorohydrate), tenidap (Enablex), Melanin (Large Scale Biological), and anti-p38 MAPK agents by Uriach. [00405] Nucleic acid molecules encoding proteins, polypeptides, or peptides with

TNF-y antagonist activity, or proteins, polypeptides, or peptides with TNF-α antagonist activity can be administered to a subject at risk of or with an inflammatory or autoimmune disease in accordance with the methods of the invention. Further, nucleic acid molecules encoding derivatives, analogs, fragments or variants of proteins, polypeptides, or peptides with TNF-y antagonist activity, or derivatives, analogs, fragments or variants of proteins, polypeptides, or peptides with TNF-α antagonist activity can be administered to a subject at risk of or with an inflammatory or autoimmune disease in accordance with the methods of the invention. Preferably, such derivatives, analogs, variants and fragments retain the TNF-α antagonist activity of the full-length, wild-type protein, polypeptide, or peptide. [00406] Proteins, polypeptides, or peptides that can be used as TNF-α antagonists can be produced by any technique well-known in the art or described herein. Proteins, polypeptides or peptides with TNF-α antagonist activity can be engineered so as to increase the in vivo half-life of such proteins, polypeptides, or peptides utilizing techniques well- known in the art or described herein. Preferably, agents that are commercially available and known to function as TNF-α antagonists are used in the compositions and methods of the invention. The TNF-α antagonist activity of an agent can be determined in vitro and/or in vivo by any technique well-known to one skilled in the art.

5.6.3.5 ANTI-CANCER AGENTS

[00407] Any therapy {e.g., therapeutic or prophylactic agent) which is known to be useful, has been used, or is currently being used for the prevention, treatment, management, or amelioration of a proliferative disorder, such as cancer (benign, malignant or metastatic), or one or more symptoms thereof can be used in compositions and method of the invention. Therapies (e.g., therapeutic or prophylactic agents) include, but are not limited to, peptides, polypeptides, fusion proteins, nucleic acid molecules, small molecules, mimetic agents, synthetic drugs, inorganic molecules, and organic molecules. Non-limiting examples of cancer therapies include chemotherapies, radiation therapies, hormonal therapies, and/or biological therapies/immunotherapies .

[00408] In certain embodiments, the anti-cancer agent is an immunomodulatory agent, such as a chemotherapeutic agent. In certain other embodiments, the anti-cancer agent is an immunomodulatory agent other than a chemotherapeutic agent. In other embodiments, the anti-cancer agent is not an immunomodulatory agent. In specific embodiments, the anticancer agent is an anti-angiogenic agent. In other embodiments, the anti-cancer agent is not an anti-angiogenic agent. In specific embodiments, the anti-cancer agent is an anti- inflammatory agent. In other embodiments, the anti-cancer agent is not an anti-inflammatory agent.

[00409] In particular embodiments, the anti-cancer agent is, but not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bisphosphonates {e.g., pamidronate (Aredria), sodium clondronate (Bonefos), zoledronic acid (Zometa), alendronate (Fosamax), etidronate, ibandornate, cimadronate, risedromate, and tiludromate); bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefmgol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-nl ; interferon alpha-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; anti-CD2 antibodies (e.g., siplizumab (Medlmmune Inc.; International Publication No. WO 02/098370, which is incorporated herein by reference in its entirety)); megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfϊn; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfm; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. [00410] Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lac tarn derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; HMG CoA reductase inhibitors (e.g., atorvastatin, cerivastatin, fluvastatin, lescol, lupitor, lovastatin, rosuvastatin, and simvastatin); hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4- iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; LFA-3TIP (Biogen, Cambridge, MA; International Publication No. WO 93/0686 and U.S. Patent No. 6,162,432); liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum- triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; suliinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; 5-fluorouracil; leucovorin; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; thalidomide; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; VITAXIN™ (see U.S. Patent Pub. No. US 2002/0168360 Al, dated November 14, 2002, entitled "Methods of Preventing or Treating Inflammatory or Autoimmune Disorders by Administering Integrin αvβ3 Antagonists in Combination With Other Prophylactic or Therapeutic Agents"); vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. [00411] In specific embodiments, radiation therapy comprising the use of x-rays, gamma rays and other sources of radiation to destroy the cancer cells is used in combination with the antibodies of the invention. In preferred embodiments, the radiation treatment is administered as external beam radiation or teletherapy, wherein the radiation is directed from a remote source. In other preferred embodiments, the radiation treatment is administered as internal therapy or brachytherapy wherein a radioactive source is placed inside the body close to cancer cells or a tumor mass.

[00412] Cancer therapies and their dosages, routes of administration and recommended usage are known in the art and have been described in such literature as the Physicians ' Desk

Reference (59^th ed., 2005).

5.7. COMPOSITIONS AND METHODS OF ADMINISTRATION 5.7.1 PHARMACEUTICAL COMPOSITIONS

[00413] The compositions of the invention include bulk drug compositions useful in the manufacture of pharmaceutical compositions {e.g., impure or non-sterile compositions) and pharmaceutical compositions (i.e., compositions that are suitable for administration to a subject or patient) which can be used in the preparation of unit dosage forms. Such compositions comprise a prophylactically or therapeutically effective amount of a prophylactic and/or therapeutic agent disclosed herein or a combination of those agents and a pharmaceutically acceptable carrier. Preferably, compositions of the invention comprise a prophylactically or therapeutically effective amount of one or more compounds identified by the methods of the invention and a pharmaceutically acceptable carrier. In a further embodiment, the composition of the invention further comprises an additional anti-cancer agent.

[00414] In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete) or, more preferably, MF59C.1 adjuvant available from Chiron, Emeryville, CA), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solut ions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.

[00415] Generally, the ingredients of compositions of the invention are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. [00416] The compositions of the invention can be formulated as neutral or salt forms.

Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. [00417] Various delivery systems are known and can be used to administer a compound identified by the methods of the invention or the combination of compounds identified by the methods of the invention and a prophylactic agent or therapeutic agent useful for preventing or treating cancer, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the antibody or antibody fragment, receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of administering a prophylactic or therapeutic agent of the invention include, but are not limited to, parenteral (e.g., intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), intratumoral, epidural, and mucosal (e.g., intranasal, inhaled, and oral routes) administration. In a specific embodiment, prophylactic or therapeutic agents of the invention are administered intramuscularly, intravenously, or subcutaneously. The prophylactic or therapeutic agents may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g. , oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

[00418] In a specific embodiment, it may be desirable to administer the prophylactic or therapeutic agents of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion, by injection, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

[00419] In yet another embodiment, the prophylactic or therapeutic agent can be delivered in a controlled release or sustained release system. In one embodiment, a pump may be used to achieve controlled or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, polymeric materials can be used to achieve controlled or sustained release of the compound identified by the methods of the invention (see e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Am. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 7 1:105); U.S. Patent Nos. 5,679,377; 5,916,597; 5,912,015; 5,989,463; 5,128,326; International Publication Nos. WO 99/15154 and WO 99/20253. Examples of polymers used in sustained release formulations include, but are not limited to, poly(2- hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene- co-vinyl acetate), poly(methacrylic acid), polyglycolides (PLG), polyanhydrides, poly(N- vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides) (PLGA), and polyorthoesters. In a preferred embodiment, the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable. In yet another embodiment, a controlled or sustained release system can be placed in proximity of the prophylactic or therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). [00420] Controlled release systems are discussed in the review by Langer (1990,

Science 249:1527-1533). Any technique known to one of skill in the art can be used to produce sustained release formulations comprising one or more prophylactic or therapeutic agents of the invention. See, e.g., U.S. Patent No. 4,526,938; International Publication Nos. WO 91/05548 and WO 96/20698; Ning et al., 1996, Radiotherapy & Oncology 39:179-189; Song et al., 1995, PDA Journal of Pharmaceutical Science & Technology 50:372-397; Cleek et al., 1997, Pro. Int'l. Symp. Control. ReI. Bioact. Mater. 24:853-854; and Lam et al., 1997, Proc. Int'l. Symp. Control ReI. Bioact. Mater. 24:759-760, each of which is incorporated herein by reference in its entirety.

5.7.2 FORMULATIONS

[00421] Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.

[00422] Thus, the compounds identified by the methods of the invention and their physiologically acceptable salts and solvates may be formulated for administration by inhalation or insufflation (either through the mouth or the nose) or oral, parenteral, intratumoral, or mucosal (such as buccal, vaginal, rectal, sublingual) administration. In a specific embodiment local administration is used. In another embodiment, parenteral administration is used.

[00423] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl- p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

[00424] Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[00425] For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

[00426] For administration by inhalation, the prophylactic or therapeutic agents for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[00427] The prophylactic or therapeutic agents may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[00428] The prophylactic or therapeutic agents may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[00429] In addition to the formulations described previously, the prophylactic or therapeutic agents may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the prophylactic or therapeutic agents may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[00430] The invention also provides that a prophylactic or therapeutic agent is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity. In one embodiment, the prophylactic or therapeutic agent is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a subject.

[00431] The formulation and administration of various chemotherapeutic, biological/immunotherapeutic and hormonal therapeutic agents are known in the art and often described in the Physicians ' Desk Reference, 59^th ed. 2005). Radiation therapy agents such as radioactive isotopes can be given orally as liquids in capsules or as a drink. Radioactive isotopes can also be formulated for intravenous injections. The skilled oncologist can determine the preferred formulation and route of administration.

[00432] The compositions may, if desired, be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

5.7.3 DOSAGEAND FREQUENCYOFADMINISTRATION

[00433] The amount of a prophylactic or therapeutic agent or a composition of the invention which will be effective in the prevention, treatment, management, and/or amelioration of a cancer (e.g., cancer of the prostate, ovary, lung, colon, pancreas or bladder), or one or more symptoms thereof can be determined by standard clinical methods. The frequency and dosage will vary also according to factors specific for each patient depending on the specific therapies (e.g., the specific therapeutic or prophylactic agent or a gents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient. For example, the dosage of a prophylactic or therapeutic agent or a composition of the invention which will be effective in the treatment, prevention, management, and/or amelioration of cancer, or one or more symptoms thereof can be determined by administering the composition to an animal model such as, e.g., the animal models disclosed herein or known in to those skilled in the art. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. Suitable regimens can be selected by one skilled in the art by considering such factors and by following, for example, dosages are reported in literature and recommended in the Physicians ' Desk Reference (59^th ed., 2005).

[00434] Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram). For antibodies, proteins, polypeptides, peptides and fusion proteins encompassed by the invention, the dosage administered to a patient is typically 0.0001 mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosage administered to a patient is between 0.0001 mg/kg and 20 mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5 mg/kg, 0.0001 and 2 mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and 0.75 mg/kg, 0.0001 mg/kg and 0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg, 0.0001 to 0.15 mg/kg, 0.0001 to 0.10 mg/kg, 0.001 to 0.5 mg/kg, 0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kg of the patient's body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the invention or fragments thereof may be reduced by enhancing uptake and tissue penetration of the antibodies by modifications such as, for example, lipidation.

[00435] In a specific embodiment, the dosage of an antibody, polypeptide, peptide, composition of the invention administered to prevent, treat, manage, and/or ameliorate cancer, or one or more symptoms thereof in a patient is 150 μg/kg or less, preferably 125 μg/kg or less, 100 μg/kg or less, 95 μg/kg or less, 90 μg/kg or less, 85 μg/kg or less, 80 μg/kg or less, 75 μg/kg or less, 70 μg/kg or less, 65 μg/kg or less, 60 μg/kg or less, 55 μg/kg or less, 50 μg/kg or less, 45 μg/kg or less, 40 μg/kg or less, 35 μg/kg or less, 30 μg/kg or less, 25 μg/kg or less, 20 μg/kg or less, 15 μg/kg or less, 10 μg/kg or less, 5 μg/kg or less, 2.5 μg/kg or less, 2 μg/kg or less, 1.5 μg/kg or less, 1 μg/kg or less, 0.5 μg/kg or less, or 0.5 μg/kg or less of a patient's body weight. In another embodiment, the dosage of an antibody, polypeptide or peptide of the invention administered to prevent, treat, manage, and/or ameliorate cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[00436] In other embodiments, a subject is administered one or more doses of an effective amount of one or more compounds of the invention {e.g., a polypeptide or antibody), wherein the dose of an effective amount achieves a serum titer of at least 0.1 μg/ml, at least 0.5 μg/ml, at least 1 μg/ml, at least 2 μg/ml, at least 5 μg/ml, at least 6 μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25 μg/ml, at least 50 μg/ml, at least 100 μg/ml, at least 125 μg/ml, at least 150 μg/ml, at least 175 μg/ml, at least 200 μg/ml, at least 225 μg/ml, at least 250 μg/ml, at least 275 μg/ml, at least 300 μg/ml, at least 325 μg/ml, at least 350 μg/ml, at least 375 μg/ml, or at least 400 μg/ml of the antibodies of the invention. In yet other embodiments, a subject is administered a dose of an effective amount of one or more compounds identified by the methods of the invention to achieve a serum titer of at least 0.1 μg/ml, at least 0.5 μg/ml, at least 1 μg/ml, at least, 2 μg/ml, at least 5 μg/ml, at least 6 μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25 μg/ml, at least 50 μg/ml, at least 100 μg/ml, at least 125 μg/ml, at least 150 μg/ml, at least 175 μg/ml, at least 200 μg/ml, at least 225 μg/ml, at least 250 μg/ml, at least 275 μg/ml, at least 300 μg/ml, at least 325 μg/ml, at least 350 μg/ml, at least 375 μg/ml, or at least 400 μg/ml of the compounds identified by the methods of the invention and a subsequent dose of an effective amount of one or more compounds identified by the methods of the invention is administered to maintain a serum titer of at least 0.1 μg/ml, 0.5 μg/ml, 1 μg/ml, at least, 2 μg/ml, at least 5 μg/ml, at least 6 μg/ml, at least 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25 μg/ml, at least 50 μg/ml, at least 100 μg/ml, at least 125 μg/ml, at least 150 μg/ml, at least 175 μg/ml, at least 200 μg/ml, at least 225 μg/ml, at least 250 μg/ml, at least 275 μg/ml, at least 300 μg/ml, at least 325 μg/ml, at least 350 μg/ml, at least 375 μg/ml, or at least 400 μg/ml. In accordance with these embodiments, a subject may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more subsequent doses.

[00437] In a specific embodiment, the invention provides methods of preventing, treating, managing, or treating cancer or one or more symptoms thereof, said method comprising administering to a subject in need thereof a dose of at least 10 μg, preferably at least 15 μg, at least 20 μg, at least 25 μg, at least 30 μg, at least 35 μg, at least 40 μg, at least 45 μg, at least 50 μg, at least 55 μg, at least 60 μg, at least 65 μg, at least 70 μg, at least 75 μg, at least 80 μg, at least 85 μg, at least 90 μg, at least 95 μg, at least 100 μg, at least 105 μg, at least 110 μg, at least 115 μg, or at least 120 μg of one or more antibodies, polypeptides or peptides of the invention. In another embodiment, the invention provides a method of preventing, treating, managing, and/or ameliorating cancer or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 10 μg, preferably at least 15 μg, at least 20 μg, at least 25 μg, at least 30 μg, at least 35 μg, at least 40 μg, at least 45 μg, at least 50 μg, at least 55 μg, at least 60 μg, at least 65 μg, at least 70 μg, at least 75 μg, at least 80 μg, at least 85 μg, at least 90 μg, at least 95 μg, at least 100 μg, at least 105 μg, at least 110 μg, at least 115 μg, or at least 120 μg of one or more antibodies, polypeptides or peptides of the invention once every 3 days, preferably, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month. [00438] The present invention provides methods of preventing, treating, managing, or preventing cancer or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof one or more doses of a prophylactically or therapeutically effective amount of one or more antibodies, polypeptides or peptides of the invention; and (b) monitoring the plasma level/concentration of the said administered antibody or antibodies in said subject after administration of a certain number of doses of the said antibodies, polypeptides or peptides. Moreover, preferably, said certain number of doses is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses of a prophylactically or therapeutically effective amount one or more antibody, polypeptide or peptide compositions of the invention. [00439] In a specific embodiment, the invention provides a method of preventing, treating, managing, and/or ameliorating cancer or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof a dose of at least 10 μg (preferably at least 15 μg, at least 20 μg, at least 25 μg, at least 30 μg, at least 35 μg, at least 40 μg, at least 45 μg, at least 50 μg, at least 55 μg, at least 60 μg, at least 65 μg, at least 70 μg, at least 75 μg, at least 80 μg, at least 85 μg, at least 90 μg, at least 95 μg, or at least 100 μg) of one or more antibodies, polypeptides or peptides of the invention; and (b) administering one or more subsequent doses to said subject when the plasma level of the antibodies, polypeptides or peptides administered in said subject is less than 0.1 μg/ml, preferably less than 0.25 μg/ml, less than 0.5 μg/ml, less than 0.75 μg/ml, or less than 1 μg/ml. In another embodiment, the invention provides a method of preventing, treating, managing, and/or ameliorating cancer or one or more symptoms thereof, said method comprising: (a) administering to a subject in need thereof one or more doses of at least 10 μg (preferably at least 15 μg, at least 20 μg, at least 25 μg, at least 30 μg, at least 35 μg, at least 40 μg, at least 45 μg, at least 50 μg, at least 55 μg, at least 60 μg, at least 65 μg, at least 70 μg, at least 75 μg, at least 80 μg, at least 85 μg, at least 90 μg, at least 95 μg, or at least 100 μg) of one or more antibodies, polypeptides or peptides of the invention; (b) monitoring the plasma level of the administered antibody or antibodies of the invention in said subject after the administration of a certain number of doses; and (c) administering a subsequent dose of the antibodies, polypeptides or peptides of the invention when the plasma level of the administered antibodies, polypeptides or peptides in said subject is less than 0.1 μg/ml, preferably less than 0.25 μg/ml, less than 0.5 μg/ml, less than 0.75 μg/ml, or less than 1 μg/ml. Preferably, said certain number of doses is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses of an effective amount of one or more antibodies, polypeptides or peptides of the invention. [00440] Therapies (e.g., prophylactic or therapeutic agents), other than antibodies of the invention, which have been or are currently being used to prevent, treat, manage, and/or ameliorate cancer or more symptoms thereof can be administered in combination with one or more compounds of the invention according to the methods of the invention to treat, manage, prevent, and/or ameliorate cancer or one or more symptoms thereof. Preferably, the dosages of prophylactic or therapeutic agents used in combination therapies of the invention are lower than those which have been or are currently being used to prevent, treat, manage, and/or ameliorate cancer or one or more symptoms thereof. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of cancer or one or more symptoms thereof can be obtained from any reference in the art including, but not limited to, Hardman et al., eds., 2001, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics, 1 Oth ed., Mc-Graw-Hill, New York; Physicians ' Desk Reference (59^m ed., 2005), Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.

[00441] In various embodiments, the therapies (e.g. , prophylactic or therapeutic agents) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In preferred embodiments, two or more therapies are administered within the same patent visit.

[00442] In certain embodiments, one or more compounds of the invention and one or more other therapies (e.g., prophylactic or therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time, optionally, followed by the administration of a third therapy (e.g., prophylactic or therapeutic agent) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the therapies, to avoid or reduce the side effects of one of the therapies, and/or to improve the efficacy of the therapies. [00443] In certain embodiments, the administration of the same compounds of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months. In other embodiments, the administration of the same therapy (e.g., prophylactic or therapeutic agent) other than an antibody, peptide or polypeptide of the invention may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or at least 6 months . The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

5.8. KITS [00444] One embodiment of the present invention comprises kits for measuring the expression of at least 1, at least 2, at least 3, or any combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib. Such kits comprise materials and reagents required for measuring the expression of such genes, e.g., measuring the amount of mRNA or protein or fragments thereof. In some embodiments, such kits include reagents for dot blotting, micoarrays, primers for RT-PCR, ICAT™-MS/MS and immunohistochemistry (e.g., Western blotting).

[00445] The invention provides kits that are useful for detecting, diagnosing, monitoring and prognosing cancer based upon the expression of at least 1, at least 2, at least 3, or any combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP 13Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRJA4, 0R4M1, KIAA1679 and/or UPK-Ib in a sample. [00446] The invention provides kits useful for monitoring the efficacy of one or more therapies that a subject is undergoing based upon the expression of at least 1, at least 2, at least 3, or any combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib in a sample.

[00447] The invention provides kits using for determining whether a subject will be responsive to a therapy based upon the expression of at least 1, at least 2, at least 3, or any combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib in a sample.

[00448] The invention provides kits for measuring the expression of at least I, at least

2, at least 3, or a combination of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ 12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib. In a specific embodiment, such kits comprise materials and reagents that are necessary for measuring the expression of the nucleic acid sequences. For example, a microarray or RT-PCR kit may be produced for cancer and contain only those reagents and materials necessary for measuring the levels of RNA transcripts of at least one of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAAl 244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. Alternatively, in some embodiments, the kits can comprise materials and reagents that are not limited to those required to measure the expression of the nucleic acid sequences of one or more of the following: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATPl 3 A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib. For example, a microarray kit may contain reagents and materials necessary for measuring the levels of RNA transcripts of genes whose expression do not necessarily associated with or indicative of cancer, in addition to reagents and materials necessary for measuring the levels of the RNA transcripts at least I, at least 2, at least 3, or a combinantion of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC 15668, MGC33486, TMEMl 6F, FAT, KIAAO 195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJl 2443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib.

[00449] For nucleic acid micoarray kits, the kits generally comprise probes attached to a solid support surface. The probes may be labeled with a detectable label. In a specific embodiment, the probes are specific for SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, 0CIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib nucleic acid sequences. The microarray kits may comprise instructions for performing the assay and methods for interpreting and analyzing the data resulting from the performance of the assay. In a specific embodiment, the kits comprise instructions for diagnosing cancer. The kits may also comprise hybridization reagents and/or reagents necessary for detecting a signal produced when a probe hybridizes to a target nucleic acid sequence. Generally, the materials and reagents for the microarray kits are in one or more containers. Each component of the kit is generally in its own a suitable container. [00450] For RT-PCR kits, the kits generally comprise pre-selected primers specific for particular nucleic acid sequences (i.e., one or more of the following nucleic acid sequences: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib. The RT-PCR kits may also comprise enzymes suitable for reverse transcribing and/or amplifying nucleic acids (e.g., polymerases such as Taq), and deoxynucleotides and buffers needed for the reaction mixture for reverse transcription and amplification. The RT-PCR kits may also comprise probes specific for one or more of the following nucleic acid sequences: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19or£26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, OR4M1, KIAA1679 and/or UPK-Ib. The probes may or may not be labeled with a detectable label (e.g., a fluorescent label). Each component of the RT-PCR kit is generally in its own suitable container. Thus, these kits generally comprise distinct containers suitable for each individual reagent, enzyme, primer and probe. Further, the RT-PCR kits may comprise instructions for performing the assay and methods for interpreting and analyzing the data resulting from the performance of the assay. In a specific embodiment, the kits contain instructions for diagnosing cancer.

[00451] For antibody based kits, the kit can comprise, for example: (1) a first antibody

(which may or may not be attached to a solid support) which binds to a peptide, polypeptide or protein of interest (e.g., one or more of the following proteins: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, CHorflόO, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 and/or UPK-Ib); and, optionally, (2) a second, different antibody which binds to either the peptide, polypeptide or protein, or the first antibody and is conjugated to a detectable label (e.g., a fluorescent label, radioactive isotope or enzyme). In a specific embodiment, the peptide, polypeptide or protein of interest is associated with or indicative of cancer. The antibody-based kits may also comprise beads for conducting an immunoprecipitation. Each component of the antibody-based kits is generally in its own suitable container. Thus, these kits generally comprise distinct containers suitable for each antibody. Further, the antibody-based kits may comprise instructions for performing the assay and methods for interpreting and analyzing the data resulting from the performance of the assay. In a specific embodiment, the kits contain instructions for diagnosing cancer. [00452] In order that the invention described herein may be more fully understood, the following example is set forth. It should be understood that this example is for illustrative purposes only and are not to be construed as limiting this invention in any manner.

6. EXAMPLE: IDENTIFICATION OF POTENTIAL CANCER TARGETS

[00453] The example described herein provides a method for identifying potential antigenic cancer targets, i.e., certain genes that are differentially expressed (e.g., overexpressed) in certain types of cancer, including, but not limited to, colon cancer, lung cancer, ovarian cancer, prostate cancer and/or pancreatic cancer. Exemplary methods are described in detail below and are outlined in Figure 1.

6.1. QUANTITATIVE PROTEOMICS & GENOMICS 6.1.1 ICAT-MS/MS

[00454] The relative abundance of cell surface proteins between normal and cancer

(e.g., malignant cancer) tissues was determined using isotope coded affinity tag (IC AT™) technology manner (see, e.g., Gygi et al., 1999, Nat. Biotechnol. 17:994-999; and Han et al., 2001, Nat. Biotechnol. 19:946-951, the contents of each are incorporated by reference herein in their entireties). In the first step, membrane proteins were isolated from both cancer (e.g., malignant cancer) cells and normal control cells. Sources of protein included a colon, lung, ovarian, prostate, and/or pancreatic tissue sample from subjects suffering from colon, lung, ovarian, prostate, and/or pancreatic cancer, or from normal subjects or population of normal subjects that did not have cancer. In the second step, the proteins from the cancer cells were labeled with an isotopically heavy (d9) coded affinity tag and the proteins from normal cells with an isotopically light (dθ) coded affinity tag, respectively. In a third step, N-glycosylated proteins were further purified, based on the assumption that a larger number of plasma membrane proteins are N-glycosylated and can hence be distinguished from their counterparts on internal membranes. The purified proteins were proteolyzed by trypsin and the resulting peptides were separated by multidimensional chromatography (cation exchange and avidin affinity chromatography) into multiple fractions. All fractions were analyzed by automated tandem mass spectrometry (MS/MS). The raw data was searched against protein and DNA databases and the results interpreted using software tools described herein. 6.1.2 SELECTION

[00455] For each patient sample, the raw data generated in the LC-MS/MS runs was searched against the human.nci sequence database, which currently contains over 88,000 entries, using SEQUEST (Eng et al., 1994, J. Am. Soc. Mass Spectrom. 5:976-89; Haynes et al., 1998, Electrophoresis 19:939-45, the contents of each are incorporated by reference herein in their entireties). The resulting SEQUEST output files were then combined into one large dataset and entered into the SBEAMS database, which allowed the data to be filtered based on various SEQUEST factors including cross and delta correlation scores (Xcorr and dCn), number of tryptic ends of peptide and others. SBEAMS also includes the recently developed peptide probability score, which combines various parameters including the aforementioned factors through a statistical model into one single value (Keller et al., 2002, Anal. Chem. 74:5383-92, which is incorporated by reference herein in its entirety). [00456] The data analysis focused on proteins showing differential expression between the normal and the malignant sample, with d9/dθ ratios of > 1.4. [00457] The proteins were analyzed in detail, including a determination of their subcellular location and function. For proteins with unknown function, sequence homology and/or for subcellular localization, transmembrane, and signal peptide predictions were performed. The final results are shown in Table 1 {supra).

[00458] The expression profile of the gene in normal and cancer tissue samples is assessed using any technique well-known in the art for assessing gene expression. In specific embodiments, one or more, or all of the following techniques are used: RT-PCR, dot blot analysis and immunohistochemistry. Brief descriptions of such techniques are described below.

6.1.3 RT-PCR

[00459] PCR is used to screen a panel of normalized first strand cDNA from eight normal tissues (Clontech MTC: I; brain, heart, kidney, liver, lung, skeletal muscle, pancreas, placenta). Once a target of interest is selected for expression profiling at the level of mRNA, the literature, GenBank, and/or NCBFs AceView is used to facilitate the design of primers that differentiate between known or predicted variants. Oligonucleotide primers for PCR are designed with standard features yielding a 400-500 bp PCR product. Primers span introns and anneal to regions located within the least conserved sequences of the gene. [00460] Each amplification reaction contains 2 μl cDNA, coding and non-coding primers (1 μM final concentration each), dNTPs (1 mM final concentration), and 1 unit Taq DNA polymerase in storage buffer A (Promega) in Ix Taq DNA polymerase buffer with MgCl₂. Cycling conditions include an extended denaturation at 94°C for 5 min, followed by 45 cycles of 94°C for 15 seconds, 55° - 60⁰C for 15 seconds and 72⁰C for 30 seconds. A final extension is performed at 72°C for 14 minutes. Ten μl of the amplification product is visualized using ethidium bromide and electrophoresis on a 2.5% agarose gel in 0.5x TBE. Amplification reactions using primers specific for the housekeeping gene GAPDH are set-up in parallel to assess both the efficiency of the cycling reaction and the integrity of the starting cDNA. Genes or variants with robust expression (approximately 50% or more of the expression observed with the GAPDH control) in at least two of these tissues are de- prioritized. Genes with limited expression in the normal tissue panel can be further evaluated by probing a dot blot containing normalized cDNA from matched normal and tumor specimens derived from multiple cancer patients (Clontech cancer profiling array I).

6.1.4 DOT BLOT ANALYSIS

[00461] The blot contains paired samples of normal/tumor cDNA derived from breast

(50 pairs), uterus (42), colon (35), stomach (27), ovary (14), lung (21), kidney (20), rectum (18), thyroid (6), prostate (4), small intestine (2), and pancreas (1). A collection of 10 cell lines is also present on the blot. The cancer profiling array is probed using DIG labeling and detection reagents (Roche). In brief, a digoxigenin labeled cDNA probe is synthesized using the PCR DIG Probe Synthesis Kit (Roche) according to the manufacturer's specifications. The probe synthesis reaction includes: the primers utilized for the initial PCR analysis of the target of interest, first strand cDNA determined to be positive by PCR for use as the template, and dNTPs containing a percentage of DIG-labeled dUTP. Efficient labeling of the probe is confirmed by observing a reduction in the mobility of the PCR product (relative to an unlabeled control) upon agarose gel electrophoresis.

[00462] Prior to hybridization, the cancer profiling array is sealed into a hybridization bag (Roche) and pre-hybed with 50 ml pre- warmed DIG Easy Hyb (Roche) with agitation for at least 30 minutes in a water bath. The optimal hybridization temperature is 20-25⁰C below the melting temperature which is determined using the equation T_m ⁼ 49.82 + 0.41 (% GC of probe) - (600/ probe length in bp). The entire probe synthesis reaction is boiled for 5 minutes and immediately chilled on ice. The probe is then added to 50 ml fresh, prewarmed DIG Easy Hyb and mixed by inverting. The pre-hyb buffer is discarded, and the probe hybridized overnight at the optimal temperature.

[00463] After hybridization, the probe is removed and stored at -20°C. The blot then undergoes low and high stringency washes. Two low stringency washes are performed in 2X SSC, 0.1% SDS for 5 minutes at room temperature with constant agitation. Two high stringency washes are performed in 0.1 X SSC, 0.1% SDS for 15 minutes at 65⁰C with agitation. Following the high stringency washes, the DIG probe is detected by immunoblot using buffers, an antibody and a chemiluminescent detection reagent available from Roche (DIG Wash and Block Buffer Set; Anti-Digoxigenin-AP; CDP-Star ready-to-use). Unless otherwise stated, subsequent steps are performed in 50 ml volumes at room temperature with agitation.

[00464] Briefly, the blot is washed for at least 5 minutes in Ix DIG Wash Buffer, followed by a one hour incubation in DIG Block buffer. The alkaline phosphatase (AP)- conjugated digoxigenin antibody is reacted with the blot at a 1 :20,000 dilution in fresh DIG Block buffer for 30 minutes. Two 30 minute washes are then performed with Ix DIG Wash Buffer. Prior to detection of AP activity, the blot is washed in 20 ml Ix Detection Buffer for 3 minutes. The membrane is placed DNA side up on a piece of fresh hybridization bag. Next 20 - 30 drops of CDP-Star is applied to the surface of the membrane. A second piece of hybridization bag is placed over the top of the membrane, and the substrate is spread evenly over its surface. Any air bubbles are pressed out. After a 5 minute incubation, the substrate is squeezed out of the bag, and all sides are sealed. The array is then exposed to Kodak XAR film for 15 - 25 minutes. Following chemiluminescent detection, the membrane is washed in H₂O for 1 minute. The cancer array blot is then stripped of the alkali-labile DIG-dUTP probe using two 15 minute washes in 0.2 N NaOH and 0.1% SDS at 65⁰C with agitation. The array is washed in 2x SSC for 5 minutes prior to being wrapped in plastic wrap and stored at -2O⁰C. Blots can be successfully reprobed at least 8 times. Spots on the film are then quantified with the aid of a light box. Genes that show greater expression in tumor than in the matching normal counterpart in at least 20% of the samples of a given type of tissue are moved forward to analysis at the level of protein expression. For genes with a less remarkable profile, the proteomics dataset is reviewed. If the protein is overexpressed in tumor in at least three experiments, it is considered a reasonable candidate for further validation.

6.1.5 IMMUNOHISTOCHEMISTRY [00465] Once a gene(s) of interest (e.g., SLC12A2, FLJ23375, GRM5, TAS2R1,

NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJ11848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14or£27, OSAP, FAD 104, FLJ90492, SLC27A3, RON, ATP 13Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 and/or UPK-Ib) is identified, polyclonal antisera is raised against the protein(s). Such polyclonal antisera may be used in immunohistochemistry (IHC) experiments using methods well-known to those skilled in the art to detect the expression of genes of interest in various tissue or cell types (e.g., in colon, lung, ovary, prostate and/or pancreas tissues or cells). Normal and cancer tissues are analyzed.

6.2. ANTIBODY PRODUCTION/IMMUNIZATION

[00466] Antibodies, in particular monoclonal antibodies, immunospecific for a protein encoded by a gene of interest can be generated using techniques well-known in the art. See, e.g., Section 5.6.2.2, supra. In a specific embodiment, such antibodies are generated once a gene of interest has been selected as a potential cancer target.

6.3. ZZV VITRO ASSAYS AND ANIMAL MODEL STUDIES

[00467] Once a potential cancer target has been identified, in vitro assays and animal model studies well-known in the art can be conducted to determine the efficacy of therapies that target the expression of the gene of interest. Non- limiting examples of such assays are described in Section 5.5.2, supra.

7. EQUIVALENTS

[00468] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

WHAT IS CLAIMED:

1. A method for detecting or diagnosing cancer in a subject, the method comprising: (a) determining the expression level of at least 1 of the following genes in a sample from the subject: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATPl 3Al, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib; and (b) comparing the level of expression in (a) to a corresponding control sample from a normal subject, wherein cancer is detected or diagnosed if there is an increase in the expression level of such gene in (a) relative to the expression in the control sample.

2. A method for detecting or diagnosing cancer in a subject, the method comprising: (a) determining the expression level of at least 2 of the following genes in a sample from the subject: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAAl 797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib; and (b) comparing the level of expression in (a) to a corresponding control sample from a normal subject, wherein cancer is detected or diagnosed if there is an increase in the expression level of such gene(s) in (a) relative to the expression in the control sample.

3. A method for detecting or diagnosing cancer in a subject, the method comprising: (a) determining the expression level of at least 3 of the following genes in a sample from the subject: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAAl 679 or UPK-Ib; and (b) comparing the level of expression in (a) to a corresponding control sample from a normal subject, wherein cancer is detected or diagnosed if there is an increase in the expression level of such gene(s) in (a) relative to the expression in the control sample.

4. The method of any one of claims 1-3, wherein said determining comprises determining the level of the protein products or protein product fragments of said genes.

5. The method of claim 4, wherein the increase is at least 1.5 fold, at least 2 fold, 5 fold or 10 fold.

6. The method any one of claims 1-3, wherein said sample is obtained from the colon, lung, ovary, prostate, pancreas or bladder.

7. The method of claim 5, wherein said sample is obtained from the colon, lung, ovary, prostate, pancreas or bladder.

8. A method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a test compound with a cell expressing a gene product or gene product fragment of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib; and (b) determining the ability of the test compound to bind to the gene product or gene product fragment so that if a compound binds to the gene product or gene product fragment, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified.

9. A method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a test compound with a gene product or gene product fragment of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib; and (b) determining the ability of the test compound to bind to the gene product or gene product fragment so that if a compound binds to the gene product or gene product fragment, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified.

10. A method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprising: (a) contacting a test compound with a cell expressing a gene product or gene product fragment of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib; (b) determining the amount of the gene product or gene product fragment present in (a); and (c) comparing the amount in (a) to that present in a corresponding control cell that has not been contacted with the test compound, so that if the amount of the gene product or gene product fragment is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified.

11. A method for identifying a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof, said method comprises: (a) contacting a test compound with a cell-free extract and a nucleic acid sequence comprising a nucleotide sequence encoding a gene product or gene product fragment of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PROl 855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib; (b) determining the amount of the gene product or gene product fragment present in (a); and (c) comparing the amount in (a) to that present to a corresponding control that has not been contacted with the test compound, so that if the amount of gene product or gene product fragment is altered relative to the amount in the control, a compound to be tested for its ability to prevent, treat, manage or ameliorate cancer or a symptom thereof is identified.

12. The method of any one of claims 8-11, wherein said gene product or gene product fragment comprises a protein product or protein product fragment of said gene(s).

13. The method of claim 12, wherein the expression level(s) is altered by at least 1.5 fold, at least 2 fold, 4 fold, 5 fold, 10 fold or 25 fold relative to the expression level in the control sample.

14. The method of any one of claims 8-11, wherein the compound is an antibody, an antisense molecule or a small molecule.

15. The method of any one of claims 8-11, further comprising testing the efficacy of the compound in an animal model for cancer.

16. A compound identified by the method of claim 15.

17. A method of treating cancer in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of an antibody selected from the group consisting of an anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti- NRXN2, anti-C14orfl60, anti-MGC 15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti-VEZATIN, anti- TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti- TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti- GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti~C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and anti-UPK-lb antibody.

18. The method of claim 17, wherein said cancer is a cancer of the colon, lung, ovary, prostate, pancreas or bladder.

19. The method of claim 17, wherein said cancer is a metastatic cancer.

20. The method of claim 17, wherein said cancer comprises cells that overexpress SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEMl 6F, FAT, KIAAO 195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO 1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08_; ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib relative to non-cancer cells having the tissue type of said cancer cells.

21. The method of claim 17, wherein said antibody is a monoclonal antibody.

22. The method of claim 17, wherein said antibody is humanized or chimerized.

23. The method of claim 17, wherein said antibody comprises a variant Fc region which selectively binds to a cell surface receptor of an immune effector cell selected from the group consisting of macrophages, natural killer cells, B-cells and neutrophils.

24. The method of claim 23, wherein said cell surface receptor is CD16A or CD32A.

25. The method of claim 17, comprising the administration of an additional anti-cancer therapy that is not an anti-SLC12A2, anti-FLJ23375, anti-GRM5, anti-TAS2Rl, anti- NRXN2, anti-C14orfl60, anti-MGC15668, anti-MGC33486, anti-TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti-MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti-FLJ90709, anti- VEZATIN, anti- TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orfl 8, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti-SLC39A3v2, anti-BAT5, anti- TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti-TACSTD2, anti-FNDC3A, anti- GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti-SDFRl, anti-FLJ20481, anti- LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti-C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti- FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti- C14orf27, anti-OS AP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti-RON, anti- ATP13A1, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti-KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 or anti-UPK-lb antibody.

26. The method of claim 25, wherein said additional anti-cancer therapy is selected from the group consisting of chemotherapy, biological therapy, immunotherapy, radiation therapy and surgery.

27. The method of claim 25 or 26, wherein said additional anti-cancer therapy is an anti- CD32B antibody.

28. The method of claim 27, wherein said anti-CD32B antibody is humanized or non- humanized.

29. A method of treating a cancer in a subject that is fully or partially refractory to a first treatment in a patient in need thereof, said method comprising administering to said patient a second treatment comprising administration of a therapeutically effective amount of an antibody selected from the group consisting of an anti-SLC12A2, anti-FLJ23375, anti- GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGCl 5668, anti-MGC33486, anti- TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti- MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti- FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDlLl, anti-C2orfl8, anti-ANKRD22, anti~FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti- SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti- TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti- SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ 12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-IL IRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti- C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATPlOB, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti- RON, anti-ATP13Al, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti- KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and anti-UPK-lb antibody.

30. The method of claim 29 wherein said first treatment is chemotherapy, hormonal therapy, biological therapy or radiation therapy.

31. The method of claim 29 wherein said second treatment further comprises administering chemotherapy, hormonal therapy, biological therapy or radiation therapy.

32. The method of claim 31 , comprising administering an anti-CD32B antibody.

33. The method of claim 32, wherein said anti-CD32B antibody is humanized or non- humanized.

34. The method of claim 29 which comprises administering said first treatment concurrently with administration of said second treatment.

35. The method of claim 29, wherein said antibody is a monoclonal antibody.

36. The method of claim 29, wherein said antibody is humanized or chimerized.

37. The method of claim 29, wherein said antibody comprises a variant Fc region which selectively binds to a cell surface receptor of an immune effector cell selected from the group consisting of macrophages, natural killer cells, B-cells and neutrophils.

38. The method of claim 37, wherein said cell surface receptor is CD16A or CD32A.

39. A pharmaceutical composition comprising a therapeutically effective amount of an antibody selected from the group consisting of an anti-SLC12A2, anti-FLJ23375, anti- GRM5, anti-TAS2Rl, anti-NRXN2, anti-C14orfl60, anti-MGC15668, anti-MGC33486, anti- TMEM16F, anti-FAT, anti-KIAA0195, anti-LRFN, anti-NFASC, anti-BAT2Dl, anti- MGC2963, anti-KIAA0685, anti-EDG3, anti-GGTL3, anti-PLVAP, anti-FLJ31528, anti- FLJ90709, anti- VEZATIN, anti-TMPRSS9, anti-ATP13A5, anti-PKHDILl, anti-C2orf 18, anti-ANKRD22, anti-FAM62B, anti-LOC57168, anti-CDKALl, anti-SLC39A3vl, anti- SLC39A3v2, anti-BAT5, anti-TM9SF4, anti-DC2, anti-VAPB, anti-XTP3TPB, anti- TACSTD2, anti-FNDC3A, anti-GKOOl, anti-OCIAD2, anti-PRO1855, anti-C20orf3, anti- SDFRl, anti-FLJ20481, anti-LENG4, anti-FLJ12443, anti-ARP5 Long, anti-ARP5 Short, anti-TMD0645, anti-NGEP, anti-ILlRAPl, anti-PLXNBl, anti-ATP2B2, anti-FLJ11848, anti-ENTPD2, anti-PPMlH, anti-KRTKAP3, anti-KCNC3, anti-TM9SFl, anti-ULBPl, anti- C19orf26, anti-KIAA830, anti-KIAA1244, anti-KIAA1797, anti-MGC26856, anti-NETO2, anti-SUSD2, anti-FOLR2, anti-EMR2, ENTPDl, anti-ATP10B, anti-PTK7, anti-FLJ14681, anti-C20orf22, anti-FLJ 14281, anti-FAM8Al, anti-TMED7, anti-C20orfl08, anti-ATADl, anti-GPR154, anti-C14orf27, anti-OSAP, anti-FAD104, anti-FLJ90492, anti-SLC27A3, anti- RON, anti-ATP13Al, anti-DKFZP564Dl 66, anti-ESSPL, anti-EXTL3, anti-KAIl, anti- KIAA0960, anti-MTRNL, anti-SLC27Al, anti-GRIA, anti-OR4Ml, anti-KIAA1679 and anti-UPK-lb antibody and a pharmaceutically acceptable carrier.

40. The pharmaceutical composition of claim 39, wherein said antibody is a monoclonal antibody.

41. The pharmaceutical composition of claim 39, wherein said antibody is humanized or chimerized.

42. The pharmaceutical composition of claim 39, wherein said antibody comprises a variant Fc region which selectively binds to a cell surface receptor of an immune effector cell selected from the group consisting of macrophages, natural killer cells, B-cells and neutrophils.

43. The pharmaceutical composition of claim 42, wherein said cell surface receptor is CD16A or CD32A.

44. A method for treating cancer in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of one or more therapies that modulate the expression or activity of one or more of the following genes: SLC12A2, FLJ23375, GRM5, TAS2R1, NRXN2, C14orfl60, MGC15668, MGC33486, TMEM16F, FAT, KIAA0195, LRFN, NFASC, BAT2D1, MGC2963, KIAA0685, EDG3, GGTL3, PLVAP, FLJ31528, FLJ90709, VEZATIN, TMPRSS9, ATP13A5, PKHDlLl, C2orfl8, ANKRD22, FAM62B, LOC57168, CDKALl, SLC39A3vl, SLC39A3v2, BAT5, TM9SF4, DC2, VAPB, XTP3TPB, TACSTD2, FNDC3A, GKOOl, OCIAD2, PRO1855, C20orf3, SDFRl, FLJ20481, LENG4, FLJ12443, ARP5 Long, ARP5 Short, TMD0645, NGEP, ILlRAPl, PLXNBl, ATP2B2, FLJl 1848, ENTPD2, PPMlH, KRTKAP3, KCNC3, TM9SF1, ULBPl, C19orf26, KIAA830, KIAA1244, KIAA1797, MGC26856, NETO2, SUSD2, FOLR2, EMR2, ENTPDl, ATPlOB, PTK7, FLJ14681, C20orf22, FLJ14281, FAM8A1, TMED7, C20orfl08, ATADl, GPR154, C14orf27, OSAP, FAD104, FLJ90492, SLC27A3, RON, ATP13A1, DKFZP564D166, ESSPL, EXTL3, KAIl, KIAA0960, MTRNL, SLC27A1, GRIA4, 0R4M1, KIAA1679 or UPK-Ib.