Therapeutic and diagnostic applications based on the role of the CXCR-4 gene in tumorigenesis

Abstract

The present invention relates to the identification of a novel role of CXCR-4 in cell transformation and aberrant cellular proliferation. In particular, the present invention relates to the altered gene expression of CXCR-4 in a number of primary tumors and cell lines derived from tumors, in addition to, the altered gene expression of ligands for CXCR-4. Further, the present invention relates, in part, to the Applicants' surprising discovery that the inhibition of CXCR-4 gene expression or the inhibition of CXCR-4 activity in transformed cells reverses the transformed phenotype.

1 . A pharmaceutical composition for the treatment of tumorigenesis comprising an antisense nucleic acid complementary to at least a portion of an RNA transcript of a CXCR-4 gene in an amount effective to inhibit hyperproliferation of a tumor cell.  
     
     
         2 . A pharmaceutical composition for the treatment of tumorigenesis-comprising an antibody to CXCR-4 in an amount effective to inhibit hyperproliferation of a tumor cell.  
     
     
         3 . A method of treating or preventing a disease or disorder involving cell overproliferation in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule that inhibits CXCR-4 function.  
     
     
         4 . The method according to  claim 3  in which the disease or disorder is a malignancy.  
     
     
         5 . The method according to  claim 3  in which the disease or disorder is selected from the group consisting of brain cancer, breast cancer, colon cancer, prostate cancer and B cell lymphoma.  
     
     
         6 . The method according to  claim 3  in which the subject is a human.  
     
     
         7 . The method according to  claim 5  in which the brain cancer is selected from the group consisting of glioblastoma, glioma, meningioma, astrocytoma, medulloblastoma, neuroectodermal cancer and neuroblastoma.  
     
     
         8 . The method according to  claim 6  in which the glioblastoma is glioblastoma multiforme.  
     
     
         9 . The method according to  claim 3  in which the disease or disorder is selected from the group consisting of premalignant conditions, benign tumors, hyperproliferative disorders, and benign dysproliferative disorders.  
     
     
         10 . The method according to  claim 3  in which the molecule that inhibits CXCR-4 function is selected from the group consisting of an anti-CXCR-4 antibody or a fragment thereof, a CXCR-4 derivative or analog that is capable of being bound by an anti-CXCR-4 antibody, a CXCR-4 antisense nucleic acid, and a nucleic acid comprising at least a portion of a CXCR-4 gene into which a heterologous nucleotide sequence has been inserted such that said heterologous sequence inactivates the biological activity of the at least a portion of the CXCR-4 gene, in which the CXCR-4 gene portion flanks the heterologous sequence so as to promote homologous recombination with a genomic CXCR-4 gene.  
     
     
         11 . The method according to  claim 3  in which the molecule that inhibits CXCR-4 function is an oligonucleotide which (a) consists of at least six nucleotides; (b) comprises a sequence complementary to at least a portion of an RNA transcript of a CXCR-4 gene; and (c) is hybridizable to the RNA transcript under moderately stringent conditions.  
     
     
         12 . A method of treating or preventing a disease or disorder involving cell proliferation in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a molecule that promotes CXCR-4 function.  
     
     
         13 . The method according to  claim 12 , in which the disease or disorder is selected from the group consisting of degenerative disorders, growth deficiencies, hypoproliferative disorders, physical trauma, lesions, and wounds.  
     
     
         14 . A method of diagnosing a disease or disorder characterized by an aberrant level of CXCR-4 RNA or protein in a subject, comprising measuring the level of CXCR-4 RNA or protein in a sample derived from the subject, in which an increase or decrease in the level of CXCR-4 RNA or protein, relative to the level of CXCR-4 RNA or protein found in an analogous sample not having the disease or disorder, indicates the presence of the disease or disorder in the subject.  
     
     
         15 . A method of diagnosing or screening for the presence of or a predisposition for developing a disease or disorder involving cell overproliferation in a subject comprising detecting CXCR-4 DNA, RNA or protein derived from the subject in which the presence of said CXCR-4 DNA, RNA or protein indicates the presence of the disease or disorder or a predisposition for developing the disease or disorder.  
     
     
         16 . A kit comprising in one or more containers a molecule selected from the group consisting of an anti-CXCR-4 antibody, a nucleic acid probe capable of hybridizing to a CXCR-4 RNA, or a pair of nucleic acid primers capable of priming amplification of at least a portion of a CXCR-4 nucleic acid.  
     
     
         17 . A pharmaceutical composition for the treatment of tumorigenesis comprising an antisense nucleic acid complementary to at least a portion of an RNA transcript of a SDF-1 gene in an amount effective to inhibit hyperproliferation of a tumor cell.  
     
     
         18 . A pharmaceutical composition for the treatment of tumorigenesis comprising an antibody to SDF-1 in an amount effective to inhibit hyperproliferation of a tumor cell.  
     
     
         19 . A method of treating or preventing a disease or disorder involving cell overproliferation in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule that inhibits SDF-1 function.  
     
     
         20 . A method of diagnosing a disease or disorder characterized by an aberrant level of SDF-1 RNA or protein in a subject, comprising measuring the level of SDF-1 RNA or protein in a sample derived from the subject, in which an increase or decrease in the level of SDF-1 RNA or protein, relative to the level of SDF-1 RNA or protein found in an analogous sample not having the disease or disorder, indicates the presence of the disease or disorder in the subject.  
     
     
         21 . A method of diagnosing or screening for the presence of or a predisposition for developing a disease or disorder involving cell overproliferation in a subject comprising detecting SDF-1 DNA, RNA or protein derived from the subject in which the presence of said SDF-1 DNA, RNA or protein indicates the presence of the disease or disorder or a predisposition for developing the disease or disorder.  
     
     
         22 . A kit comprising in one or more containers a molecule selected from the group consisting of an anti-SDF-1 antibody, a nucleic acid probe capable of hybridizing to a SDF-1 RNA, or a pair of nucleic acid primers capable of priming amplification of at least a portion of a SDF-1 nucleic acid.