Use of jumonji c demethylase inhibitors for the treatment and prevention of chemotherapy resistance and radioresistance in cancer

Abstract

Disclosed are methods for the use of Jumonji C demethylase inhibitors for the radiosensitization of cancers cells and the treatment and prevention of chemotherapy resistance in cancer.

1 . A method for treating cancer in a subject in need thereof, the method consisting of administering to the subject a therapeutically effective amount of an agent that inhibits a JmjC polypeptide,
 wherein the agent that inhibits a JmjC polypeptide comprises a JIB-04 or GSK-J4 derivative comprising EJMI/EMI 01, EJMI/EMI 02, EJMI 04, EPH 316, EPH 334, EPH 411, EBI01(NSC737393), EPH135, EPH294, EBI02(737394), INHE02, INHE03, INHE10, INHE23, JIB-04 E (NSC693627), NSC737393-Br, NSC693322, JK1a, JK1b, JK1c, JK1d, JK1i, JK1k, SS01138, SS01150, KK1116, KK1179, HL1132, HL1178, HL1188, HL1194, SS02035, HL1132, HL1178, HL1188, HL1194, and/or SS02035,   wherein the JIB-04 or GSK-J4 derivative is administered as a monotherapy,   wherein the cancer is non-small cell lung cancer, and   wherein the cancer is resistant to a cancer therapy.   
     
     
         2 . The method of  claim 1 , wherein the agent that inhibits a JmjC polypeptide is:
 a catalytic JmjC domain inhibitor;   a PHD domain inhibitor or a protein-protein interaction inhibitor; and/or   a pan-JmjC demethylase inhibitor or an inhibitor of two or more JmjC enzymes; and/or   wherein the agent that inhibits a JmjC polypeptide targets two or more members of the Jumonji enzyme family and/or a protein that comprises a JmjC domain.   
     
     
         3 .- 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the agent that inhibits a JmjC polypeptide inhibits one or more of KDM2A, KDM2B, KDM3A, KDM3B, KDM4A, KDM4B, KDM4C, KDM4D, KDM4E, KDM5A, KDM5B, KDM5C, KDM6A, KDM6B, PHF8, FBXL19, JMJD6, HIF1AN, MINA, and/or NO66. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the administration targets cancer therapy-resistant tumors after the development of resistance. 
     
     
         19 . The method of  claim 1 , wherein the administration prevents the emergence of resistance in cancer therapy-sensitive and/or untreated tumors. 
     
     
         20 . A method of increasing the efficacy of a cancer therapy in a subject in need thereof consisting of administering to the subject a therapeutically effective amount of an agent that inhibits a JmjC polypeptide,
 wherein the agent that inhibits a JmjC polypeptide comprises a JIB-04 or GSK-J4 derivative comprising EJMI/EMI 01, EJMI/EMI 02, EJMI 04, EPH 316, EPH 334, EPH 411, EBI01(NSC737393), EPH135, EPH294, EBI02(737394), INHE02, INHE03, INHE10, INHE23, JIB-04 E (NSC693627), NSC737393-Br, NSC693322, JK1a, JK1b, JK1c, JK1d, JK1i, JK1k, SS01138, SS01150, KK1116, KK1179, HL1132, HL1178, HL1188, HL1194, SS02035, HL1132, HL1178, HL1188, HL1194, and/or SS02035,   wherein the JIB-04 or GSK-J4 derivative is administered as a monotherapy,   wherein the cancer is non-small cell lung cancer, and   wherein the chemotherapy or radiation therapy treats a cancer that has become resistant and/or is intrinsically resistant to the cancer therapy.   
     
     
         21 . The method of  claim 20 , wherein the cancer therapy is chemotherapy or radiation therapy. 
     
     
         22 . The method of  claim 20 , wherein the cancer is radiosensitized and/or chemo sensitized. 
     
     
         23 . The method of  claim 21 , wherein the radiation therapy is x-rays and/or gamma rays. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 20 , wherein the agent that inhibits a JmjC polypeptide targets a protein that comprises a JmjC domain and/or is a pan-JmjC demethylase inhibitor or an inhibitor of two or more JmjC enzymes. 
     
     
         26 .- 29 . (canceled) 
     
     
         30 . The method of  claim 20 , wherein the agent that inhibits a JmjC polypeptide inhibits one or more of KDM2A, KDM2B, KDM3A, KDM3B, KDM4A, KDM4B, KDM4C, KDM4D, KDM4E, KDM5A, KDM5B, KDM5C, KDM6A, KDM6B, PHF8, FBXL19, JMJD6, HIF1AN, MINA, and/or NO66. 
     
     
         31 . The method of  claim 30 , wherein the agent that inhibits a JmjC polypeptide affects H3K4, H3K9, and/or H3K36 methylation. 
     
     
         32 . The method of  claim 31 , wherein the affected H3K4, H3K9, and/or H3K36 methylation results in blocking or delaying DNA repair in cancer cells that increases the efficacy of radiation. 
     
     
         33 . The method of  claim 20 , wherein the administration comprises targeting chemoresistant tumors after the development of radioresistance. 
     
     
         34 . The method of  claim 20 , wherein the administration delays or inhibits the emergence of resistance in chemo-sensitive, radio-sensitive, and/or untreated tumors. 
     
     
         35 . The method of  claim 20 , wherein the administration decreases toxicities of radiation. 
     
     
         36 . The method of  claim 1 , wherein the administration delays or inhibits the emergence of resistance in chemo-sensitive and/or untreated tumors. 
     
     
         37 . The method of  claim 1 , wherein the non-small cell lung cancer has been identified as one that has increased expression of two or more JmjC polypeptides relative to a subject having a non-small cell lung cancer that is sensitive to the chemotherapy. 
     
     
         38 . The method of  claim 21 , wherein the chemotherapy is a taxane-platin combination therapy comprising paclitaxel-carboplatin or docetaxel-cisplatin doublet therapy. 
     
     
         39 . A method for treating cancer in a subject in need thereof, the method consisting of administering to the subject a therapeutically effective amount of a JIB-04 or GSK-J4 derivative comprising EJMI/EMI 01, EJMI/EMI 02, EJMI 04, EPH 316, EPH 334, EPH 411, EBI01(NSC737393), EPH135, EPH294, EBI02(737394), INHE02, INHE03, INHE10, INHE23, JIB-04 E (NSC693627), NSC737393-Br, NSC693322, JK1a, JK1b, JK1c, JK1d, JK1i, JK1k, SS01138, SS01150, KK1116, KK1179, HL1132, HL1178, HL1188, HL1194, SS02035, HL1132, HL1178, HL1188, HL1194, and/or SS02035,
 wherein the JIB-04 or GSK-J4 derivative is administered as a monotherapy,   wherein the cancer is non-small cell lung cancer,   wherein the non-small cell lung cancer is resistant to a cancer therapy, and   wherein administration of the JIB-04 or GSK-J4 derivative targets chemoresistant tumors after the development of resistance.