Effective treatment of esophageal adenocarcinoma using triciribine and related compounds

Abstract

The inventors have determined, contrary to the prior art and experience, how to successfully use triciribine to treat esophogeal adenocarcinoma by one or a combination of (i) administering triciribine only to patients which according to a diagnostic test described below, exhibit enhanced sensitivity to the drug; (ii) use of a described dosage level that minimizes the toxicity of the drug but yet still exhibits efficacy; or (iii) use of a described dosage regimen that minimizes the toxicity of the drug.

1 - 42 . (canceled) 
     
     
         43 . A method for treating esophageal adenocarcinoma in a mammal comprising administering an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         wherein each R 2 ′ and R 3 ′ are independently hydrogen, optionally substituted phosphate or phosphonate; acyl; alkyl; amide, sulfonate ester; sulfonyl, methanesulfonyl and benzylsulfonyl, wherein the phenyl group is optionally substituted with one or more substituents; optionally substituted arylsulfonyl; a lipid, phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R 2 ′ and R 3 ′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl; amide, alkyl; aromatic, polyoxyalkylene, polyethyleneglycol, arylsulfonyl; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group; 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl, alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl. 
       
     
     
         44 . The method of  claim 43 , wherein the subject has been diagnosed with esophogeal adenocarcinoma. 
     
     
         45 . The method of  claim 43 , wherein the compound is administered one time per week for three weeks followed by a one week period wherein the compound is not administered. 
     
     
         46 . The method of  claim 45 , wherein the administration is repeated at least twice. 
     
     
         47 . The method of  claim 43 , wherein at least 10 mg/m 2  of the compound is administered. 
     
     
         48 . The method of  claim 43 , wherein 10 mg/m 2  or less of the compound is administered. 
     
     
         49 . The method of  claim 43 , wherein the the drug is administered intravenously. 
     
     
         50 . The method of  claim 43 , wherein the mammal is a human. 
     
     
         51 . A method to treat esophogeal adenocarcinoma in a mammal comprising administering to said mammal a dose of 10 mg/m 2  or less of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein each R 2 ′ and R 3 ′ are independently hydrogen, optionally substituted phosphate or phosphonate; acyl; alkyl; amide, sulfonate ester; sulfonyl, methanesulfonyl and benzylsulfonyl, wherein the phenyl group is optionally substituted with one or more substituents; optionally substituted arylsulfonyl; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R 2 ′ and R 3 ″ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl; amide, alkyl; aromatic, polyoxyalkylene, polyethyleneglycol, arylsulfonyl; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group; and 
         wherein R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl, alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl. 
       
     
     
         52 . The method of  claim 51 , wherein the administration is repeated weekly for four weeks, and wherein the four week period is followed by a one week period wherein no drug is administered. 
     
     
         53 . The method of  claim 51 , wherein the administration represents a dosing cycle. 
     
     
         54 . The method of  claim 53 , wherein the dosing cycle is repeated at least twice. 
     
     
         55 . The method of  claim 53 , wherein the dosing cycle is repeated until regression of the cancer is achieved. 
     
     
         56 . The method of  claim 51 , wherein the drug is administered intravenously. 
     
     
         57 . The method of  claim 51 , wherein the mammal is a human.