Treating bax(delta)2-positive cancer with chemotherapies targeting caspase 8

Abstract

Discovery of a new Bax isoform, BaxΔ2, in cancer cell lines and primary tumors is described. The BaxΔ2 isoform resulted from combination of Bax microsatellite mutation and alternative splicing Bax exon 2. It is also discovered that BaxΔ2 renders cancer cells sensitive to certain chemotherapeutic drugs that target caspase 8. Also provided are methods for treating colorectal cancer by administering to a colorectal cancer patient a chemotherapeutic agent that is capable of activating caspase 8, wherein the patient contains a cancer cell that expresses a BaxΔ2 protein (SEQ ID NO. 2).

1 . A method for identifying a colorectal cancer patient suitable for a therapy comprising a chemotherapeutic agent that is capable of activating caspase 8, wherein the chemotherapeutic agent is not doxorubicin, the method comprising detecting, in a cancer cell of the patient, the expression of a BaxΔ2 protein (SEQ ID NO. 2). 
     
     
         2 . The method of  claim 1 , wherein the chemotherapeutic agent is an antimetabolite. 
     
     
         3 . The method of  claim 2 , wherein the antimetabolite is a pyrimidine analog. 
     
     
         4 . The method of  claim 2 , wherein the antimetabolite is selected from the group consisting of 5-fluorouracil, hydroxyurea, doxifluridine, capecitabine, tegafur, raltitrexed, nolatrexed, LY231514, ZD9331 and combination thereof. 
     
     
         5 . The method of  claim 4 , wherein the antimetabolite is 5-fluorouracil or hydroxyurea. 
     
     
         6 . The method of  claim 1 , wherein the colorectal cancer is colon cancer. 
     
     
         7 . The method of  claim 1 , further comprising, prior to the detection, isolating the cancer cell from the patient. 
     
     
         8 . The method of  claim 1 , wherein the detection uses an antibody having specificity to the BaxΔ2 protein. 
     
     
         9 . The method of  claim 1 , wherein the detection comprises detecting a RNA sequence encoding the BaxΔ2 protein. 
     
     
         10 . The method of  claim 9 , wherein the RNA sequence comprises SEQ ID NO. 1. 
     
     
         11 . A method for identifying a colorectal cancer patient suitable for a therapy comprising a chemotherapeutic agent that is capable of activating caspase 8, wherein the chemotherapeutic agent is not doxorubicin, the method comprising detecting, in a cancer cell of the patient, the expression of a BaxΔ2 protein (SEQ ID NO. 2) with an antibody having specificity to the BaxΔ2 protein. 
     
     
         12 . The method of  claim 11 , further comprising administering to the patient the therapy. 
     
     
         13 . A method for identifying a colorectal cancer patient suitable for a therapy comprising a chemotherapeutic agent that is capable of activating caspase 8, wherein the chemotherapeutic agent is not doxorubicin, the method comprising detecting, in a cancer cell of the patient, a nucleotide sequence comprising SEQ ID NO. 1. 
     
     
         14 . The method of  claim 13 , further comprising administering to the patient the therapy.