SAB as a Biomarker for Degenerative Diseases and Therapeutic Sensitivity in Cancers

Abstract

The current invention pertains to a method of diagnosing a disease or identifying an increased likelihood of developing the disease in a subject. The method comprises determining the level of Src homology 3 domain binding protein 5 (SH3BP5 or SAB) or the RNA encoding SAB protein in a biological sample obtained from the subject and identifying the subject as having the disease or having an increased likelihood of developing the disease if the biological sample obtained from the subject has an altered level of SAB protein or the RNA encoding SAB protein relative to a control sample. The methods of the current invention can be practiced to diagnose and treat a systemic degenerative disease, a neurodegenerative disease, obesity, diabetes, a cancer, or an aging related disease. The invention also provides a kit for diagnosing a disease or diagnosing an increased likelihood of developing the disease in a subject.

We claim: 
     
         1 . A method of diagnosing a disease, or identifying an increased likelihood of developing the disease, and optionally, treating or preventing the disease in a subject, the method comprising the steps of:
 a) determining the level of Src homology 3 domain binding protein 5 (SH3BP5 or SAB) or the RNA encoding SAB protein in a biological sample obtained from the subject;   b) determining the level of SAB protein or the RNA encoding SAB protein in a control sample;   c) identifying the subject as having the disease or having an increased likelihood of developing the disease compared to an individual known to have a low likelihood of developing the disease if the biological sample obtained from the subject has an altered level of SAB protein or the RNA encoding SAB protein relative to the level of SAB protein or the RNA encoding SAB protein in the control sample; and, optionally,   d) selecting a treatment for the disease for the subject identified as having the disease or having an increased likelihood of developing the disease; and, optionally,   e) administering the treatment for the disease to the subject identified as having the disease or having an increased likelihood of developing the disease.   
     
     
         2 . The method of  claim 1 , wherein the disease is selected from a systemic degenerative disease, a neurodegenerative disease, obesity, diabetes, a cancer, and an aging related disease. 
     
     
         3 . The method of  claim 2 , wherein the systemic degenerative disease is selected from muscular dystrophy, muscular atrophy, cancer, multiple systems atrophy, multiple sclerosis, atherosclerosis, degenerative heart disease, diabetes, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, chronic obstructive pulmonary disease, prostatitis, osteoporosis, and keratoconus. 
     
     
         4 . The method of  claim 2 , wherein the neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Niemann Pick disease, and progressive supranuclear palsy, and essential tremor. 
     
     
         5 . The method of  claim 2 , wherein the cancer is susceptible to treatment using apoptosis inducing chemotherapeutic agents and/or radiation treatments. 
     
     
         6 . The method of  claim 2 , wherein the aging related disease is selected from sarcopenia, frailty, fatiguability, and cognitive decline. 
     
     
         7 . The method of  claim 1 , wherein the subject is a human. 
     
     
         8 . The method of  claim 1 , wherein the biological sample and/or the control sample is a tissue sample or a body fluid sample. 
     
     
         9 . The method of  claim 8 , wherein the body fluid sample is selected from aqueous humour, vitreous humour, bile, blood, blood serum, blood plasma, cerebrospinal fluid, endolymph, perilymph, exudates, lymph, mucus, pericardial fluid, pleural fluid, or synovial fluid. 
     
     
         10 . The method of  claim 1 , wherein the control sample is:
 a) a sample obtained from an individual known to be free from the disease or having a low likelihood of developing the disease,   b) a sample obtained from the subject when the subject was known to be free from the disease or was known to have a low likelihood of developing the disease, and/or   c) a sample containing SAB protein or the RNA encoding SAB protein at the level known to indicate the absence of the disease or a low likelihood of developing the disease.   
     
     
         11 . A kit for diagnosing a disease or diagnosing an increased likelihood of developing the disease in a subject, the kit comprising an agent that selectively binds to SAB protein or RNA encoding SAB protein and one or more reagents for measuring the binding of the agent to SAB protein or RNA encoding SAB protein present in a biological sample. 
     
     
         12 . The kit of  claim 11 , wherein the agent that selectively binds to SAB protein is an antibody or a fragment of the antibody that specifically binds to SAB protein. 
     
     
         13 . The kit of  claim 11 , wherein the antibody is conjugated to a fluorescent molecule, a radioactive molecule, an enzyme, a fluorogenic substrate, or a chromogenic substrate. 
     
     
         14 . A method of protecting a subject from toxicity associated with an apoptosis inducing chemotherapeutic agent, the method comprising administering to the subject an inhibitor of SAB-mediated signaling in an amount sufficient to delay and/or prevent non-specific toxicity associated with the apoptosis inducing chemotherapeutic agents. 
     
     
         15 . The method of  claim 14 , wherein the inhibitor of SAB-mediated signaling inhibits the expression and/or activity of SAB protein. 
     
     
         16 . A method of assessing susceptibility of a cancer in a subject to a chemotherapeutic treatment and optionally, treating the subject with the chemotherapeutic treatment for the cancer, the method comprising the steps of:
 a) determining the level of SAB protein or the RNA encoding SAB protein in a biological sample obtained from the subject;   b) determining the level of SAB protein or the RNA encoding SAB protein in a control sample;   c) identifying the subject as being susceptible to the chemotherapeutic treatment if the biological sample obtained from the subject has an increased level of SAB protein or the RNA encoding SAB protein relative to the level of SAB protein or the RNA encoding SAB protein in the control sample; and, optionally,   d) administering the chemotherapeutic treatment for the cancer to the subject identified as being susceptible to the chemotherapeutic treatment.   
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from leukemia, bladder cancer, bone cancer, brain tumor, central nervous system tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, gastrointestinal cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, liver cancer, Hodgkin lymphoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lymphoma, AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, ovarian cancer, testicular cancer, and vaginal cancer. 
     
     
         18 . The method of  claim 16 , wherein the biological sample from the subject comprises cancer cells obtained from the subject. 
     
     
         19 . A method for identifying an agent for increasing the effectiveness of a cancer treatment by increasing mitochondrial priming, the method comprising the steps of:
 a) screening potential compounds for their ability that increases SAB expression in a cell,   b) optionally, screening the potential compounds for their ability to increase mitochondrial membrane depolarization, and   b) identifying a compound capable of increasing SAB expression and/or increase mitochondrial membrane depolarization as the agent for increasing the effectiveness of a cancer treatment.   
     
     
         20 . The method of  claim 19 , wherein the cell is a cancer cell. 
     
     
         21 . A method of increasing the effectiveness of a cancer treatment administered to a subject, the method comprising administering to the subject an agent which increases SAB expression in the cancer cells of the subject. 
     
     
         22 . The method of  claim 21 , wherein the cancer is leukemia, bladder cancer, bone cancer, brain tumor, central nervous system tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, gastrointestinal cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, liver cancer, Hodgkin lymphoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lymphoma, AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, ovarian cancer, testicular cancer, and vaginal cancer. 
     
     
         23 . The method of  claim 21 , wherein the agent which increases SAB expression in the cancer cells of the subject is 2-Morpholin-4-yl-8-phenylchromen-4-one.