Fra-1 expression in brain cancer

Abstract

Fra-1 serves as a target for diagnosing and treating glioblastoma multiforme and related brain cancers. Cancer in a brain tissue sample is detected by analyzing expression of Fra-1 in the sample. Brain cancer is treated by modulating Fra-1 gene expression in cells of the cancer, and by inhibiting angiogenesis associated with the cancer by interfering with Fra-1 binding to a VEGF-D promoter.

1 . A method for detecting a cancer in a brain tissue sample, the method comprising the steps of: 
 (A) providing the brain tissue sample; and    (B) analyzing the brain tissue sample for a Fra-1 marker.    
   
   
       2 . The method of  claim 1 , wherein the step (B) of analyzing the brain tissue sample comprises comparing the quantity of expression of the Fra-1 marker to a first sample known to express detectable levels of the Fra-1 marker and a second sample known to not express detectable levels of the Fra-1 marker.  
   
   
       3 . The method of  claim 1 , wherein the Fra-1 marker is a Fra-1 nucleic acid.  
   
   
       4 . The method of  claim 3 , wherein the Fra-1 marker is an RNA.  
   
   
       5 . The method of  claim 3 , wherein the Fra-1 nucleic acid is a native Fra-1 nucleic acid.  
   
   
       6 . The method of  claim 3 , wherein the step (A) of providing a tissue sample comprises obtaining the brain tissue sample from a human subject; and the step (B) of analyzing the brain tissue sample comprises isolating RNA from the tissue sample, generating cDNAs from the isolated RNA, amplifying the cDNAs by PCR to generate a PCR product.  
   
   
       7 . The method of  claim 3 , wherein the step (A) of providing a brain tissue sample comprises obtaining the tissue sample from a human subject; and the step (B) of analyzing the brain tissue sample comprises isolating nucleic acid from the tissue sample, and contacting the isolated nucleic acid with an oligonucleotide probe that hybridizes under stringent hybridization conditions to the Fra-1 nucleic acid.  
   
   
       8 . The method of  claim 7 , wherein the oligonucleotide probe further comprises a detectable label.  
   
   
       9 . The method of  claim 1 , wherein the Fra-1 marker is a Fra-1 protein.  
   
   
       10 . The method of  claim 9 , wherein the Fra-1 protein is a native Fra-1 protein.  
   
   
       11 . The method of  claim 9 , wherein the step (A) of providing a brain tissue sample comprises obtaining the brain tissue sample from a human subject; and the step (B) of analyzing the brain tissue sample comprises contacting at least a portion of the brain tissue sample with a probe that specifically binds to the Fra-1 protein.  
   
   
       12 . The method of  claim 11 , wherein the probe comprises a detectable label.  
   
   
       13 . The method of  claim 11 , wherein the probe comprises an antibody.  
   
   
       14 . The method of  claim 13 , wherein the antibody is a polyclonal antibody.  
   
   
       15 . The method of  claim 13 , wherein the antibody is a monoclonal antibody.  
   
   
       16 . A method of modulating Fra-1 gene expression in a brain cancer cell comprising the steps of: 
 (A) providing a brain cancer cell that expresses a Fra-1 gene; and    (B) introducing into the cell an agent that modulates the expression of the Fra-1 gene in the cell.    
   
   
       17 . The method of  claim 16 , wherein the agent is an oligonucleotide.  
   
   
       18 . The method of  claim 16 , wherein the agent is an antisense oligonucleotide.  
   
   
       19 . The method of  claim 18 , wherein the antisense oligonucleotide hybridizes under stringent hybridization conditions to a polynucleotide that encodes a Fra-1 protein.  
   
   
       20 . A method of inhibiting VEGF-D gene expression in a brain cancer cell comprising the steps of: 
 (A) providing a brain cancer cell that expresses a VEGF-D gene promoter and a Fra-1 protein; and    (B) introducing into the cell an agent that interferes with binding of the Fra-1 protein to the VEGF-D gene promoter.    
   
   
       21 . The method of  claim 20 , wherein the agent specifically binds a c-Jun protein.  
   
   
       22 . The method of  claim 20 , wherein the agent specifically binds Fra-1 protein.  
   
   
       23 . The method of  claim 20 , wherein the agent specifically binds the VEGF-D promoter.  
   
   
       24 . The method of  claim 20 , wherein the agent is a variant of a native c-Jun protein that binds the Fra-1 protein but lacks the ability to bind a VEGF-D gene promoter.  
   
   
       25 . The method of  claim 20 , wherein the molecule is a variant of a native Fra-1 protein that binds a c-Jun protein but lacks the ability to bind a VEGF-D gene promoter.  
   
   
       26 . The method of  claim 20 , wherein the step (B) of introducing an agent that interferes with binding of the Fra-1 protein comprises introducing an expression vector having a nucleic acid encoding the agent into the cell.  
   
   
       27 . The method of  claim 26 , wherein the agent is an antisense oligonucleotide that hybridizes under stringent conditions to a polynucleotide that encodes a Fra-1 protein.  
   
   
       28 . The method of  claim 26 , wherein the agent is a variant of a native c-Jun protein that binds the Fra-1 protein but lacks the ability to bind a VEGF-D gene promoter.  
   
   
       29 . The method of  claim 26 , wherein the agent is a variant of a native Fra-1 protein that binds the c-Jun protein but lacks the ability to bind a VEGF-D gene promoter.  
   
   
       30 . The method of  claim 20 , wherein the brain cancer cell is contained within the cranium of a human subject.  
   
   
       31 . The method of  claim 30 , wherein the agent is administered to the human subject by parenteral administration.  
   
   
       32 . The method of  claim 31 , wherein the parenteral administration is intravenous or intraarterial injection.  
   
   
       33 . The method of  claim 32 , wherein the agent is introduced by injection into the cranium of the human subject.  
   
   
       34 . A method of identifying a test compound that modulates expression of a Fra-1 gene in a brain cancer cell, the method comprising the steps of: 
 (A) providing a brain cancer cell expressing a Fra-1 gene;    (B) contacting the cell with the test compound; and    (C) detecting a modulation in the expression of the Fra-1 gene, wherein detecting the modulation indicates that the test compound modulates expression of the Fra-1 gene.    
   
   
       35 . The method of  claim 34 , wherein the cell is derived from a tissue sample isolated from a human brain.  
   
   
       36 . The method of  claim 34 , wherein the step of detecting the modulation in the expression of the Fra-1 gene comprises analyzing the cell for a change in the amount of a Fra-1 marker in the cell.  
   
   
       37 . The method of  claim 36 , wherein the Fra-1 marker is a Fra-1 nucleic acid.  
   
   
       38 . The method of  claim 37 , wherein the Fra-1 nucleic acid is an RNA.  
   
   
       39 . The method of  claim 37 , wherein the Fra-1 nucleic acid is a native Fra-1 nucleic acid.  
   
   
       40 . The method of  claim 36 , wherein the Fra-1 marker is a Fra-1 protein.  
   
   
       41 . The method of  claim 40 , wherein the Fra-1 protein is a native Fra-1 protein.  
   
   
       42 . A method for inhibiting angiogenesis associated with a brain cancer in a subject, the method comprising the steps of: 
 (A) providing an agent that interferes with Fra-1 binding to a VEGF-D gene promoter; and    (B) administering the agent to the central nervous system of the subject in an amount effective to inhibit blood vessel development associated with the brain cancer.    
   
   
       43 . The method of  claim 42 , wherein the agent specifically binds a c-Jun protein.  
   
   
       44 . The method of  claim 42 , wherein the agent specifically binds a Fra-1 protein  
   
   
       45 . The method of  claim 42 , wherein the agent specifically binds the VEGF-D gene promoter.  
   
   
       46 . The method of  claim 42 , wherein the agent is a variant of a native c-Jun protein that binds the Fra-1 protein but lacks the ability to bind a VEGF-D gene promoter.  
   
   
       47 . The method of  claim 42 , wherein the agent is a variant of a native Fra-1 protein that binds a c-Jun protein but lacks the ability to bind a VEGF-D gene promoter.