Dehydroacetic Acid (DHAA) and Derivative for Uses in Treating Cancer

Abstract

This disclosure relates to methods of managing or treating cancer with agents that lower circulating acetoacetate levels, such as hypolipidemic agents, or other agents that antagonize acetoacetate-BRAF V600 mutant binding to attenuate BRAF V600 mutant tumor growth. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering an effective amount of an agent to a subject in need thereof, wherein the agent is dehydroacetic acid, derivative, prodrug, or salt thereof.

1 . A method of treating cancer comprising administering an effective amount of an agent to a subject in need thereof, wherein the agent lowers circulating acetoacetate levels. 
     
     
         2 . The method of  claim 1 , wherein the agent that lower circulating acetoacetate levels is a hypolipidemic agent. 
     
     
         3 . The method of  claim 1 , wherein the hypolipidemic agent is selected from a statin, fibrate, niacin, bile acid sequestrant, ezetimibe, lomitapide, phytosteriol, orlistat, CEPT inhibitor, squalene synthase inhitior, ApoA-1 Milano, succinobucol, Mipomersen, PCSK9 monoclonal antibody inhibitors. 
     
     
         4 . A method of treating cancer comprising administering an effective amount of an agent that antagonize acetoacetate-BRAF V600 mutant binding to attenuate BRAF V600 mutant tumor growth to a subject in need thereof. 
     
     
         5 . A method of treating cancer comprises administering an effective amount of dehydroacetic acid, derivative, or salt thereof to a subject in need thereof. 
     
     
         6 . The method of  claim 5 , wherein dehydroacetic acid, derivative, or salt thereof is of the following formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is O, S, or NH; 
         X is O, S, or NH; 
         Y is O, S, or NH; 
         Z is OH, SH, or NH 2  optionally substituted with one or more, the same or different, R 10 ; 
         R 1  is hydrogen, halogen, alkyl, halogenated alkyl, formyl, carboxy, hydroxyalkyl, thioalkyl, aminoalkyl, alkanoyl, alkoxycarbonyl, alkyl sulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein le is optionally substituted with one or more, the same or different, R 10 ; 
         R 2  is hydrogen, halogen, alkyl, halogenated alkyl, formyl, carboxy, hydroxyalkyl, thioalkyl, aminoalkyl, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 10 ; 
         R 3  is hydrogen, alkyl, halogenated alkyl, formyl, carboxy, hydroxyalkyl, thioalkyl, aminoalkyl, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 3  is optionally substituted with one or more, the same or different, R 10 ; and 
         R 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, hydroxyalkyl, alkylthio, thioalkyl, alkylamino, aminoalkyl, (alkyl) 2 amino, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, benozyl, benzyl, aryl, or heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 11 ; and 
         R 11  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, hydoxymethyl, hydroxyethyl, thiomethyl, thioethyl, aminomethyl, aminoethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, N-methylsulfamoyl, N-ethyl sulfamoyl, N,N-dimethyl sulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benozyl, benzyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         7 . The method of  claim 5 , wherein the neoplasm has a mutation encoding a V600E amino acid substitution present in the coding sequence for B-Raf. 
     
     
         8 . The method of  claim 5  wherein the subject is suffering from metastatic melanoma. 
     
     
         9 . The method of  claim 5 , wherein dehydroacetic acid, derivative, or salt thereof is administered in combination with a second therapeutic agent. 
     
     
         10 . A method of treating cancer comprising in a subject diagnose with cancer by limiting dietary fat intake. 
     
     
         11 . The method of  claim 10 , wherein the method further comprises measuring circulating acetoacetate levels in a blood sample from the subject. 
     
     
         12 . The method of  claim 11 , wherein the acetoacetate levels are compared to a threashold value and wherein if acetoacetate levels are above the threashold value, then dietary fat intake is decreased. 
     
     
         13 . The method of  claim 11 , wherein the subject is diagnosed with a mutation encoding a V600E amino acid substitution present in the coding sequence for B-Raf. 
     
     
         14 . The method of  claim 13 , wherein the subject is diagnosed with metastatic melanoma. 
     
     
         15 . The method of  claim 13 , wherein subject is diagnosed with a BRAF V600E-positive malignant or premalignant lesions.