JAB1 as a prognostic marker and a therapeutic target for human cancer

Abstract

Methods of diagnosing and prognosticating the development of human cancers, such as breast cancer, colon cancer, and pancreatic cancer, are provided. The diagnostic and prognostic methods include the detection and/or quantifying of the amount of expression of JAB1 in human cells, particularly in relation to the amount of p27 or c-Jun. In addition, methods for reducing the expression of JAB1 protein in cells and inhibiting its interaction with p27 or c-Jun, for example, are provided.

1 . A method of diagnosing, or determining a prognosis for, cancer in an individual, the method comprising assessing the JAB1 level in one or more cancer cells, or cells suspected of being cancerous, of the individual, wherein the cancer is breast cancer, non-Hodgkins lymphoma, colon cancer, prostate cancer, pancreatic cancer, or lung cancer.  
     
     
         2 . The method of  claim 1 , wherein the one or more cells is obtained from a sample from the individual.  
     
     
         3 . The method of  claim 1 , wherein the assessing step comprises comparing the JAB1 level the cell to the JAB1 level in a non-cancerous sample.  
     
     
         4 . The method of  claim 3 , wherein the non-cancerous sample is obtained from the individual.  
     
     
         5 . The method of  claim 3 , wherein when the JAB1 expression level is higher in the cell compared to the JAB1 expression level in the non-cancerous sample, the cell is cancerous.  
     
     
         6 . The method of  claim 1 , wherein the assessing step is further defined as assessing the ratio of JAB1/p27 level in the cell.  
     
     
         7 . The method of  claim 6 , wherein when the ratio of JAB1/p27 comprises high JAB1 expression and low p27 expression, the cell is cancerous.  
     
     
         8 . The method of  claim 7 , wherein when the ratio of JAB1/p27 expression is greater than 1, the cell is cancerous.  
     
     
         9 . The method of  claim 6 , wherein the assessing step is further defined as assessing the ratio of JAB1 polypeptide/p27 polypeptide.  
     
     
         10 . The method of  claim 6 , wherein the assessing step is further defined as assessing the ratio of JAB1 polynucleotide/p27 polynucleotide.  
     
     
         11 . The method of  claim 1 , wherein the assessing step provides information of the stage of the cancer.  
     
     
         12 . The method of  claim 11 , wherein when the JAB1 level is greater in the cell compared to the JAB1 level in a non-cancerous sample, the cell is an advanced stage cancer cell.  
     
     
         13 . The method of  claim 11 , wherein the assessing step is further defined as determining the subcellular localization of JAB1, p27, or both.  
     
     
         14 . The method of  claim 13 , further defined as identifying the ratio of JAB1 expression in the nucleus compared to the cytoplasm.  
     
     
         15 . The method of  claim 6 , wherein the assessing step provides information of the stage of the cancer.  
     
     
         16 . The method of  claim 15 , wherein when the ratio of JAB1/p27 comprises high JAB1 expression and low p27 expression, the sample comprises advanced stage cancer.  
     
     
         17 . A method of treating cancer, comprising: 
 diagnosing or determining prognosis for a cancer in accordance with any one of claims  1 - 17 ;    determining an appropriate therapy based on said diagnosis or determination of prognosis; and    treating a patient with the therapy.    
     
     
         18 . The method of  claim 17 , wherein the treating step comprises delivering a JAB1-inhibiting agent to the individual.  
     
     
         19 . The method of  claim 18 , wherein the JAB1-inhibiting agent is delivered directly to one or more cancerous cells of the individual.  
     
     
         20 . The method of  claim 18 , wherein the JAB1-inhibiting agent comprises a polynucleotide, a polypeptide, a peptide, a small molecule, or a mixture thereof.  
     
     
         21 . The method of  claim 20 , wherein the JAB1-inhibiting agent comprises a polynucleotide.  
     
     
         22 . The method of  claim 21 , wherein the polynucleotide comprises antisense JAB1 sequence.  
     
     
         23 . The method of  claim 22 , wherein the antisense JAB1 polynucleotide is further defined as being comprised on a vector, said polynucleotide being operably linked to a promoter suitable for regulation of the polynucleotide in said cancer cell.  
     
     
         24 . The method of  claim 23 , wherein the vector is a viral vector or a non-viral vector.  
     
     
         25 . The method of  claim 24 , wherein the viral vector comprises an adenoviral vector, a retroviral vector, an adeno-associated viral vector, a lentiviral vector, or a herpesviral vector.  
     
     
         26 . A method for identifying the stage of a cancer in an individual, comprising: 
 assessing the ratio of JAB1/p27 level in a cancer cell from the individual; and    determining the stage of the cancer based on said assessment.    
     
     
         27 . The method of  claim 26 , wherein when the ratio of JAB1/p27 is high, the stage of the cancer is late stage.  
     
     
         28 . A method for monitoring treatment of a cancer for an individual, said cancer characterized by a high JAB1/p27 ratio, comprising: 
 determining the JAB1/p27 ratio in at least one cancerous cell from a tissue from the individual prior to the treatment;    administering the treatment to the individual; and    determining the JAB1/p27 ratio in a cell from the tissue from the individual subsequent to the treatment.    
     
     
         29 . The method of  claim 28 , wherein the treatment comprises delivering a JAB1-inhibiting agent to the individual.  
     
     
         30 . The method of  claim 28 , wherein when the determination of the JAB1/p27 ratio in a cell from the individual subsequent to the treatment is lower than the JAB1/p27 ratio in the cancerous cell from the individual prior to the treatment, said treatment is efficacious for the cancer.  
     
     
         31 . A method of treating cancer in an individual, comprising delivering a JAB1-inhibiting agent to the individual.  
     
     
         32 . The method of  claim 31 , wherein the cancer is further defined as comprising a high JAB1/p27 level.  
     
     
         33 . The method of  claim 31 , wherein the JAB1-inhibiting agent is delivered directly to the cancer.  
     
     
         34 . The method of  claim 31 , wherein the delivery comprises intratumoral injection, microinjection, electroporation, liposomal delivery, by catheter, or a combination thereof.  
     
     
         35 . The method of  claim 31 , wherein the JAB1-inhibiting agent comprises a polynucleotide, a polypeptide, a peptide, a small molecule, or a mixture thereof.  
     
     
         36 . The method of  claim 31 , wherein the JAB1-inhibiting agent comprises a polynucleotide.  
     
     
         37 . The method of  claim 36 , wherein the polynucleotide comprises antisense JAB1 sequence.  
     
     
         38 . The method of  claim 37 , wherein the antisense JAB1 polynucleotide is further defined as being comprised on a vector, said polynucleotide being operably linked to a promoter suitable for regulation of the polynucleotide in a cancerous cell.  
     
     
         39 . The method of  claim 38 , wherein the vector is a viral vector or a non-viral vector.  
     
     
         40 . The method of  claim 39 , wherein the viral vector comprises an adenoviral vector, a retroviral vector, an adeno-associated viral vector, a lentiviral vector, or a herpesviral vector.  
     
     
         41 . A method of screening for a JAB1-inhibiting agent, comprising: 
 providing a JAB1 polypeptide;    providing a p27 polypeptide; and    providing a test compound, wherein when the test compound inhibits binding of the JAB1 polypeptide to the p27 polypeptide, said test compound is said JAB1-inhibiting agent.    
     
     
         42 . The method of  claim 41 , wherein binding of the JAB1 polypeptide to the p27 polypeptide is detected by color, fluorescence, radioactivity, or particle emission.  
     
     
         43 . The method of  claim 41 , further comprising the step of delivering the JAB1-inhibiting agent to an individual having cancer.  
     
     
         44 . A kit, housed in a suitable container, comprising a JAB1-inhibiting agent identified by the method of  claim 41 .  
     
     
         45 . A composition comprising a JAB1-inhibiting agent.  
     
     
         46 . The composition of  claim 45 , wherein the agent is a polynucleotide, polypeptide, peptide, small molecule, or a mixture thereof.  
     
     
         47 . The composition of  claim 46 , wherein the polynucleotide comprises antisense JAB1 sequence.  
     
     
         48 . The composition of  claim 46 , wherein the peptide comprises a p27-binding domain on JAB1.  
     
     
         49 . The composition of  claim 46 , wherein the peptide comprises a c-Jun-binding domain on JAB1.  
     
     
         50 . The composition of  claim 45 , comprised in a pharmaceutically acceptable diluent.  
     
     
         51 . A method of treating cancer in an individual, comprising delivering to the individual a viral vector comprising JAB1 siRNA.  
     
     
         52 . The method of  claim 51 , wherein the viral vector comprises an adenoviral vector, a retroviral vector, a lentiviral vector, a herpesviral vector, or an adeno-associated viral vector.  
     
     
         53 . A composition comprising a viral vector including antisense JAB1 sequence.  
     
     
         54 . The composition of  claim 53 , wherein the antisense JAB1 sequence comprises JAB1 siRNA.  
     
     
         55 . The composition of  claim 53 , wherein the viral vector comprises an adenoviral vector, a retroviral vector, a lentiviral vector, a herpesviral vector, or an adeno-associated viral vector.  
     
     
         56 . The composition of  claim 55 , wherein the viral vector is an adenoviral vector.