Retinoic acid receptor gamma agonists to attenuate anthracycline-induced cardiotoxicity

Abstract

Disclosed are methods, pharmaceutical compositions, kits, and systems for treating or preventing cardiotoxicity in a subject undergoing treatment with an anthracycline chemotherapeutic agent. The methods, pharmaceutical compositions, kits, and systems typically include or utilize an agonist of the retinoic acid receptor gamma (RARG).

I claim: 
     
         1 . A method for treating or preventing cardiotoxicity in a subject undergoing treatment with an anthracycline chemotherapeutic agent, the method comprising administering to the subject an agonist of the retinoic acid receptor gamma (RARG). 
     
     
         2 . The method of  claim 1 , wherein the subject has a cell proliferative disease or disorder selected from the group consisting of bladder cancer, breast cancer, glioblastoma, lymphoma, leukemia, lung cancer, ovarian cancer, pancreatic cancer, soft tissue sarcoma, and thyroid cancer. 
     
     
         3 . The method of  claim 1 , wherein the subject has the T-allele of the single nucleotide polymorphism (SNP) rs2229774 (p.Ser427Leu). 
     
     
         4 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent intercalates within DNA and prevents the release of topoisomerase 2β (TOP2B) from DNA bound to the TOP2B. 
     
     
         5 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, and aldoxorubicin. 
     
     
         6 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent is doxorubicin and in the treatment method the subject is administered a maximum cumulative dose of doxorubicin that is greater than about 400 mg/m 2 , 450 mg/m 2 , 500 mg/m 2 , 550 mg/m 2 , or 600 mg/m 2 . 
     
     
         7 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent is daunorubicin and in the treatment method the subject is administered a maximum cumulative dose of daunorubicin that is greater than about 500 mg/m 2 , 550 mg/m 2 , 600 mg/m 2 , 650 mg/m 2 , or 700 mg/m 2 . 
     
     
         8 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent is epirubicin and in the treatment method the subject is administered a maximum cumulative dose of epirubicin that is greater than about 800 mg/m 2 , 850 mg/m 2 , 900 mg/m 2 , 950 mg/m 2 , or 1000 mg/m 2 . 
     
     
         9 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent is idarubicin and in the treatment method the subject is administered intravenously a maximum cumulative dose of idarubicin that is greater than about 100 mg/m 2 , 125 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , or 200 mg/m 2 . 
     
     
         10 . The method of  claim 1 , wherein the anthracycline chemotherapeutic agent is idarubicin and in the treatment method the subject is administered orally a maximum cumulative dose of idarubicin that is greater than about 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 450 mg/m 2 , or 500 mg/m 2 . 
     
     
         11 . The method of  claim 1 , wherein the RARG agonist represses expression of TOP2B. 
     
     
         12 . The method of  claim 1 , wherein the RARG agonist is a selective agonist for the RARG. 
     
     
         13 . The method of  claim 1 , wherein the RARG agonist is selected from the group consisting of Palovarotene™ (4-[(E)-2-[5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]ethenyl]benzoic acid), AC 261066 (4-[4-(2-Butoxyethoxy-)-5-methyl-2-thiazolyl]-2-fluorobenzoic acid); AC 55649 (4′-Octyl-[1,1′-biphenyl]-4-carboxylic acid); adapalene (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); AM 580 (4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoic acid); AM 80 (4-[[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl]benzoic acid); BMS 753 (4-[[(2,3-Dihydro-1,1,3,3-tetramethyl-2-oxo-1H-inden-5-yl)carbonyl]amino]benzoic acid); BMS 961 (3-Fluoro-4-[[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydro-2-naphthalenyl)acetyl]amino]-benzoic acid); CD1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid); CD 2314 (5-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-3-thiophenecarboxylic acid); CD437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD55 (4-[(1E)-3-[3,5-bis(1,1-Dimethylethyl)phenyl]-3-oxo-1-propenyl]benzoic acid); isotretinoin (13-cis-retinoic acid); retinoic acid or all trans retinoic acid (ATRA) (3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2E,4E,6E,8E,-nonatetraenoic acid); tazarotene (6-[2-(3,4-Dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethynyl]-3-pyridinecarboxylic acid); and TTNPB (4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid). 
     
     
         14 . The method of  claim 1  comprising administering the RARG agonist prior to administering the anthracycline chemotherapeutic agent. 
     
     
         15 . The method of  claim 1  comprising administering the RARG agonist concurrently with administering the anthracycline chemotherapeutic agent. 
     
     
         16 . The method of  claim 1  comprising administering the RARG agonist after administering the anthracycline chemotherapeutic agent. 
     
     
         17 . The method of  claim 1 , wherein the subject is no more than 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 years of age. 
     
     
         18 . A pharmaceutical composition comprising a combination of an anthracycline chemotherapeutic agent and an agonist of the retinoic acid receptor gamma (RARG). 
     
     
         19 . A kit or treatment system comprising as components an anthracycline chemotherapeutic agent and an agonist of the retinoic acid receptor gamma (RARG).