MDA-9 and uses thereof

Abstract

Increased expression of MDA-9 is associated with drug resistance of certain cells (e.g., cancer cells). The invention provides methods for identifying drug resistant cells by measuring the expression or activity of MDA-9, methods for identifying modulators of drug resistance, and methods for modulating drug resistance by modulating the expression or activity of MDA-9.

What is claimed is:  
     
         1 . A method for determining whether a test compound modulates the drug resistance of a cell, the method comprising: 
 a) determining the level of MDA-9 expression in a cell in the presence of a test compound;    b) determining the level of MDA-9 expression in the cell in the absence of the test compound; and    c) identifying the compound as a modulator of drug resistance of the cell if the level of expression of MDA-9 in the cell in the presence of the test compound differs from the level of expression of MDA-9 in the cell in the absence of the test compound.    
     
     
         2 . The method of  claim 1  wherein the MDA-9 is encoded by an endogenous gene.  
     
     
         3 . A method for determining whether a test compound modulates the drug resistance of a cell, the method comprising: 
 a) incubating MDA-9 protein in the presence of a test compound;    b) determining whether the test compound binds to the MDA-9 protein;    c) selecting a test compound which binds to the MDA-9 protein;    d) administering the test compound selected in step c) to a non-human mammal having drug resistant cells;    e) determining whether the test compound alters the drug resistance of the cells in the non-human mammal; and    f) identifying the test compound as a modulator of drug resistance of the cell if the compound alters the drug resistance of the cells in step (e).    
     
     
         4 . A method for determining whether a test cell has a drug-resistant phenotype, the method comprising: 
 a) measuring the expression of MDA-9 in the test cell;    b) comparing the expression of MDA-9 measured in step a) to the expression of MDA-9 in a control cell not having a drug-resistant phenotype; and    c) determining that the test cell has a drug resistant phenotype if the expression of MDA-9 in the test cell is greater than the expression of MDA-9 in the control cell.    
     
     
         5 . A method of determining whether a test cell has a drug-resistant phenotype, the method comprising: 
 a) measuring the activity of MDA-9 in the test cell;    b) comparing the activity of MDA-9 measured in step a) to the activity of MDA-9 in a control cell not having a drug-resistant phenotype; and    c) determining that the test cell has a drug resistant phenotype if the activity of MDA-9 in the test cell is greater than the activity of MDA-9 in the control cell.    
     
     
         6 . A method for determining whether a subject has or is at risk of developing a drug resistant tumor, the method comprising: 
 a) measuring the expression of MDA-9 mRNA in a biological sample obtained from the subject;    b) comparing the expression of MDA-9 mRNA measured in step a) to the expression of MDA-9 mRNA in a biological sample obtained from a control subject not having a drug resistant tumor; and    c) determining that the patient has or is at risk of developing a drug resistant tumor if the expression of MDA-9 mRNA in the biological sample obtained from the patient is higher than the expression of MDA-9 mRNA in the biological sample obtained from the control subject.    
     
     
         7 . The method of  claim 6 , wherein step a) comprises the use of a nucleic acid molecule that hybridizes to MDA-9 mRNA.  
     
     
         8 . A method for determining whether a subject has or is at risk of developing a drug resistant tumor, the method comprising: 
 a) measuring the activity of MDA-9 in a biological sample obtained from the subject;    b) comparing the activity of MDA-9 measured in step a) to the expression of MDA-9 mRNA in a biological sample obtained from a control subject not having a drug resistant tumor; and    c) determining that the patient has or is at risk of developing a drug resistant tumor if the activity of MDA-9 in the biological sample obtained from the patient is higher than the activity of MDA-9 in the biological sample obtained from the control subject.    
     
     
         9 . The method of  claim 8 , wherein step a) comprises the use of an agent that binds to MDA-9 protein.  
     
     
         10 . A method for monitoring the effect of an anti-tumor treatment on a patient, the method comprising: 
 a) measuring the expression of MDA-9 in a tumor sample obtained from the patient;    b) comparing the expression of MDA-9 measured in step a) to the expression of MDA-9 in a control sample of cells; and    c) determining that the anti-tumor treatment should be discontinued or modified if the expression of MDA-9 in the tumor sample is higher than the expression of MDA-9 in the control sample of cells.    
     
     
         11 . The method of  claim 10 , wherein step a) comprises the use of a nucleic acid molecule that hybridizes to MDA-9 mRNA.  
     
     
         12 . A method for monitoring the effect of an anti-tumor treatment on a patient, the method comprising: 
 a) measuring the activity of MDA-9 in a tumor sample obtained from the patient;    b) comparing the activity of MDA-9 measured in step a) to the activity of MDA-9 in a control sample of cells; and    c) determining that the anti-tumor treatment should be discontinued or modified if the activity of MDA-9 in the tumor sample is higher than the activity of MDA-9 in the control sample of cells.    
     
     
         13 . The method of  claim 12 , wherein step a) comprises the use of an agent that binds to MDA-9 protein.  
     
     
         14 . A method for modulating the drug resistance of a cell, the method comprising modulating MDA-9 expression within the cell.  
     
     
         15 . A method reducing the drug resistance of cell, the method comprising contacting the cell with a molecule which reduces the expression of MDA-9 within the cell.  
     
     
         16 . A method of increasing the effectiveness of a chemotherapeutic compound in a patient suffering from a disorder associated with the presence of drug-resistant neoplastic cells, the method comprising: 
 a) administering a chemotherapeutic compound to the patient; and    b) administering a compound with reduces MDA-9 expression to the patient.    
     
     
         17 . A method of treating a mammal suspected of having a disorder associated with the presence of drug-resistant cells, the method comprising administering to the mammal a compound that reduces the expression of MDA-9 in the drug-resistant cells, the reduction be sufficient to reduce the drug resistance of the drug resistant cells.  
     
     
         18 . A method for increasing the drug resistance of cell that has an undesirably low level of MDA-9 expression, the method comprising exposing the cell to a compound that increases the expression of MDA-9.  
     
     
         19 . A method for treating a drug resistant tumor in a patient, the method comprising administering to said subject an amount of a MDA-9 antagonist effective to reduce drug resistance of said tumor in the patient.  
     
     
         20 . The use of an inhibitor of MDA-9 expression, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the treatment of a drug resistant tumor in a patient.