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Nr-cam gene, nucleic acids and nucleic acid products for therapeutic and diagnostic uses for tumorsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.)Nr-cam gene, nucleic acids and nucleic acid products for therapeutic and diagnostic uses for tumors description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070004655, Nr-cam gene, nucleic acids and nucleic acid products for therapeutic and diagnostic uses for tumors. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present application is entitled to and claims priority benefits of U.S. application Ser. No. 60/083,152, filed Apr. 27, 1998; and Ser. No. 60/112,098, filed Dec. 14, 1998, the entire disclosures of which are incorporated herein by reference. 1. FIELD OF THE INVENTION [0002] The present invention relates to the identification of a novel role for the neuron-glia-related cell adhesion molecule (Nr-CAM) gene in tumorigenesis, in particular primary brain tumorigenesis. The present invention is related to the role of Nr-CAM nucleic acids and polypeptides as diagnostic tools to indicate a pre-cancerous condition or cancer, and therapeutic agents based thereon to inhibit Nr-CAM gene expression and/or activity as a method of treating, inhibiting and/or preventing tumorigenesis. 2. BACKGROUND OF THE INVENTION 2.1. Brain Tumors [0003] Brain tumors are among the leading cause of death among young children and adults. A survey by the American Cancer Society has documented that 13,300 people died of brain tumors in 1995 and predicated that over 17,900 would die in 1996 (Parker et al., 1996, CA Cancer J. Clin., 46:5-28). The number of deaths due to brain tumors has been increasing at a significant rate each year. On average, 25,000 Americans are diagnosed with brain cancer yearly. Brain tumors claim the lives of more children than any other form of cancer except leukemia. [0004] The increased incidence of brain tumors is not only evident in children but also in adults. It has been documented that a significant increase in mortality has occurred in adult primary malignant tumors between 1982 and 1996 (Parker et al., 1996). Glioblastomas, astrocytomas and meningiomas are the most common brain tumors that affect adults (Thapar and Laws, 1993, CA Cancer J. Clin., 43:263-271). [0005] The transformation of normal human brain cells into gliomas occurs as a result of the accumulation of a series of cellular and genetic changes (Sehgal, 1998, Cancer Surv., 25:233-275; vonDiemiling et al., 1995, Glia 15:328-338; Furnari et al., 1995, J. Surg. Oncol. 67:234). These genetic alterations include the loss, gain or amplification of different chromosomes. These genetic changes lead to altered expression of proteins that play important roles in the regulation of normal cell proliferation. Several common genetic alternations at the chromosomal level (loss of 17p, 13q, 9p, 19, 10, 22q, 18q and amplification of 7 and 12q) have been observed (Sehgal et al., 1998 J. Surg. Oncol. 67:23; vonDiemiling et al., 1995, Glia 15:328-338; Furnari et al., 1995, Cancer Surv. 25:233-275). These alterations lead to changes in the expression of several genes (p53, RB, INF.alpha./.beta., CDKN2, MMAC1, DCC, EGFR, PDGF, PDGFr, MDM2, GLI, CDK4 and SAS) during the genesis and progression of human gliomas (Sehgal, 1998, J. Surg. Oncol. 67:234; vonDiemiling et al., 1995, Glia 15:328-338). Recent studies have suggested that altered expression of several other genes (MET, MYC, TGF.beta., CD44, VEGF, N-CAML1, p21.sup.waf1/CiP1, trka, MMRs, C4-2, D2-2) and proteins (cathepsins, tenascin, matrix metalloproteases, tissue inhibitors of metalloproteases, nitric oxide synthetase, integrins, IL 13 receptor, Connexin 43, uPAR's extracellular matrix proteins and heat shock proteins) are associated with the genesis of human gliomas (Sehgal, 1998, J. Surg. Oncol. 67:234). Taken together these findings point to the fact that accumulation of multiple genetic mutations coupled with extensive changes in gene expression may be a prerequisite in the etiology of human gliomas. Despite identification of these genetic alterations, the exact series of events that leads to the genesis of human gliomas is not clear. [0006] Glioblastoma multiforme are high grade astrocytomas that grow very rapidly and contain cells that are very malignant (Thapar and Laws, 1993, CA Cancer J. Clin., 43:263-271). The molecular basis of glioblastoma multiforme occurrence may involve systematic events at the chromosomal level or at a gene expression level. These may include inactivation of tumor suppressor genes, activation of oncogenes or specific translocations at the chromosomal level. Some genetic changes at the chromosomal level and gene expression level have been well documented for other brain tumors (Furnari et al., 1995, Cancer Surv., 25:233-275). For example, it has been documented that loss of tumor suppressor(s) genes at chromosome 10, mutations in p53, or overexpression of epidermal growth factor receptor, may be major events leading to glioblastoma multiforme. A number of other genes such as EGFR, CD44, .beta.4 integrins, membrane-type metalloproteinase (MT-MMP), p21, p16, p15, myc, and VEGF have been shown to be overexpressed in different types of brain tumors (Faillot et al., 1996, Neurosurgery, 39:478-483; Eibl et al., 1995, J. Neurooncol., 26:165-170; Previtali et al., 1996, Neuropathol. Exp. Neurol. 55:456-465; Yamamoto et al., 1996, Cancer Res., 56:384-392; Jung et al., 1995, Oncogene, 11:2021-2028; Tsuzuki et al., 1996, Cancer, 78:287-293; Chen et al., 1995, Nature Med., 1:638-643; Takano, et al., 1996, Cancer Res., 56:2185-2190; Bogler et al., 1995, Glia, 15:308-327). Several cell adhesion molecules (CAMs), such as integrins, cadherins, IgSF proteins (carcinoembryonic antigen, N-CAM and VCAM-1) or lectins, are thought to be involved in tumorigenesis (Johnson, 1991, Cancer Metastat. Rev. 10:11-22). Over-expression of anti-sense to the secreted glycoprotein SPRAC (secreted protein, acidic and rich in cysteine), results in suppression of the adhesive and invasive capacities of melanomas (Ledda et al., 1997, Nature (Med). 3:171-176). The cell-surface adhesion molecule MCAM(MUC18) when over-expressed may lead to increased adhesion and metastatic potential of human melanoma cells in nude mice (Xie et al., 1997, Proc. Nat'l Cancer Conf. 38:522). Expression of N-CAM or ICAM (Intracellular adhesion molecule) is related inversely to increased metastasis (Hortsch, 1996, Neuron 17:587-593). Other genes such as p53 show mutations in the majority of brain tumors (Bogler et al., supra). How the interplay of one or more of these genes leads to tumorigenesis is not known but most likely multiple steps are required for neoplastic transformation. The exact series of events that lead to initiation or progression of glioblastoma are not known at present and useful markers for early detection of brain tumors are lacking. 2.2. CAMs [0007] A subfamily of the immunoglobulin superfamily (IgSF) proteins are termed "cell adhesion molecules" (CAMs) (Hortsch, 1996, Neuron 17:587-593). [0008] Several CAM family members are implicated in the process of tumorigenesis including, N-CAM, CEA, (Cacinoembryonic Antigen), DCC (Deleted in Colon Carcinoma) and L1. [0009] CEA is a cell surface glycoprotein of colon mucosal cells. High levels of CEA are observed in the serum of tumor patients (Benchimol, et al., 1989, Cell, 57:327-334). It was demonstrated that over-expression of CEA in malignant cells may disturb intercellular adhesion that may in turn cause tissue disruption leading to the metastasis of primary tumor cells (Albelda, 1993, Lab Invest, 68:4-14; Benchimol et al., 1989). [0010] L1 is another cell adhesion molecule that belongs to the Ig superfamily and is expressed in neuroblastomas, melanomas, lymphocytes and Schwann cells (Izumoto, et al., 1996, Cancer Res, 56:1440-1444). Antibody neutralization experiments demonstrate that L1 is responsible for the highly invasive nature of the C6 glioma cells. Mutations in the L1 are known to be associated with a spectrum of neurological deficiencies including mental retardation (Izumoto et al., 1996). [0011] The neural cell adhesion molecules (N-CAMs) are predominantly though not exclusively, expressed in developing peripheral and central nervous systems of a number of invertebrates and vertebrates. These proteins are generally present on the cell surface and consist of multiple Ig domains, multiple fibronectin type III repeats near the cell membrane and either a transmembrane domain or a glycophosphatidylinositol-linked membrane anchor at the C-terminus (Hortsch, 1996). The N-CAMs can be grouped into 2 major structural families, one resembling N-CAM and the other resembling the liver CAM (L-CAM) and its mammalian homologue uvomorulin or E-cadherins. Within N-CAM, 2 major types are observed, the N-CAM (neuronal CAM) and the neuron-glial CAM (Ng-CAM) (Grumet et al., 1991, J. Cell Biol. 113:1399-1412). [0012] N-CAM is expressed in a wide variety of tissues and is implicated in embryonic development. Over-expression of N-CAM is observed in a variety of tumors including multiple myelomas, small cell carcinomas and adenoid cystic carcinomas. Down regulation of N-CAM is observed in malignant glioma cells (Albelda, 1993; Poley, et al., 1997, Anticancer Research, 17:3021-3024). In Wilm's tumor of kidney, the N-CAM exists in h-PSA form that is less adhesive to surrounding cells and fibers. In a recent study it was demonstrated that high levels of N-CAM were detected in patients with prostate carcinomas (Lynch, et al., 1997, Prostate, 32:214-220). In vivo studies in nude mice demonstrated that N-CAM may be involved not only in adhesive and motile behavior of cells but also in their growth regulation (Poley et al., 1997; Lynch et al., 1997). [0013] DCC is a cell adhesion molecule that belongs to the N-CAM family. DCC was first shown to be expressed in a variety of tumors including the brain and lung but its expression was reduced and mutated in a number of colorectal carcinomas (Fearon, et al., 1990, Cell, 61:759-767). The down regulation or mutation of the DCC molecule lead to the disruption of normal cell-cell adhesion in the intestinal epithelium. This process is known to play an important role in the metastasis of colorectal carcinomas (Albelda, 1993; Fearon et al., 1990). 2.2.1. Nr-CAM [0014] Nr-CAM (neuron-glia related CAM) was cloned from a chicken brain library when Ng-CAM cDNA Clones were being isolated (Grumet et al., 1991, J. Cell Biol. 113:1399-1412). Monoclonal antibodies against E8 tectal surface protein identified a similar molecule that was cloned from a chicken brain library. This protein was designated Bravo/Nr-CAM (Grumet et al., 1991; Lane et al., 1986, Genomics 35:456-465). The Nr-CAM protein contains 6 Ig domains and 5 fibronectin repeats. Numerous studies on chicken Nr-CAM suggested that it may play an important role in cell-cell adhesion during the development of the vertebrate nervous system. The human homologue of the chicken Nr-CAM has been cloned (Lane et al., 1996, Genomics 35:456-465; see Lane et al., FIG. 1 at pages 458-9 for nucleotide and deduced amino acid sequences of hNr-CAM, incorporated herein by reference). [0015] Sequence analysis of Nr-CAM proteins isolated from human rat, chicken, and mouse showed more than 80% identity. One unique characteristic of hNr-CAM is that the third fibronectin repeat contains a furin-like cleavage site (Grumet, 1991, Current Opinion in Neurobiology, 1:370-376; Suter, et al., 1995, J. Cell Biol., 131:1067-1081). It has also been reported that the 140KDa protein may exist as a doublet (Grumet, et al., 1991, J. Cell Biol., 113:1399-1412; Lane, et al., 1996, Genomics, 35:456-465). [0016] The cytoplasmic tail of the hNr-CAM protein is known to interact with a cytoplasmic protein named ankyrin (Davis, et al., 1993, J. Cell Biol., 121:121-133; Davis, et al., 1996, J. Cell Biol., 135:1355-1367). This region of the hNr-CAM protein is highly conserved among other family members (Ng-CAM, L1, neurofascin and neuroglian protein). Neurofascin and L1 proteins contain a phosphorylation site that may modulate its interaction with ankyrin (Davis, 1993; Davis 1996). Phosphorylation status of hNr-CAM in this region of the protein has not been reported yet. The cytoplasmic tail of the hNr-CAM contains sequences that have potential to interact with PSD-95/discs- large/ZO-1 family of membrane associated proteins (Grumet, et al., 1991, J Cell Biol, 113:1399-1412). [0017] cDNA analysis of rat Nr-CAM revealed two different forms of Nr-CAM as a result of alternative mRNA splicing. The alternatively spliced form of Nr-CAM contains 10-amino acids inserted between the Ig domain and fibronectin domain, and 15-amino-acids inserted after the fourth fibronectin repeat, and complete deletion of the fifth fibronectin repeat (Suter et al., 1995). The extracellular portion of the Nr-CAM protein contains twenty potential sites for N-linked glycosylation (Kayyem, et al., 1992, J Cell Biol, 118:1259-1270; Suter et al., 1995; Grumet, 1991; Cell Tissue Res. 290:423-428). [0018] Nr-CAM is expressed in growing neurites and radial cells of the optic chiasm. Nr-CAM protein family members not only play an important role in cell adhesion but they can interact with other proteins, such as FGF-R, by phosphorylation events to bring about neurite extension. L1-CAM gene mutation may be involved in several neurological disorders (Hortsch, 1996). A number of transformed cells from a variety of tissues also express L1-CAM, and the expression is correlated inversely with the metastatic capacity of a lymphoma cell line in mice, leading to speculation that these CAMs may play a role in metastatic events (Hortsch, 1996). See generally, Albelda, 1993, Lab. Invest. 68:4-14. [0019] It has been demonstrated that hNr-CAM is a brain specific protein and is expressed on neurons, Schwann cells, Muller cells and transiently in the cells of floor plate (Davis, et al., 1996, J Cell Biol, 135:1355-1367; Grumet, Cell Tissue Res, [1991] 290:423-428). The hNr-CAM protein is expressed preferentially on fiber tracts, in spinal cord, cerebellum, tectum, and telencephalon. It is also known to be concentrated in the node of Ranvier, thus demonstrating its potential role in the formation and maintenance of the nodes (Suter, et al., 1995, J Cell Biol, 131:1067-1081). The hNr-CAM is also expressed widely in the retina on cell bodies and fiber layers and on the ganglion cells (Suter et al., 1995; Davis, et al., 1994, J Biol Chem, 269:27163-27166). Continue reading about Nr-cam gene, nucleic acids and nucleic acid products for therapeutic and diagnostic uses for tumors... 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