Effective treatment of ovarian cancer using triciribine and related compounds

Abstract

The inventors have determined, contrary to the prior art and experience, how to successfully use triciribine to treat ovarian cancer 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. The invention further encompasses a number of miRNAs, which are altered in human ovarian cancer, with the most significantly deregulated miRNAs being miR-214, -199a*, -200a, -100, -12Sb, and let-7 cluster. Further, the invention illustrates that frequent deregulation of miR-214, -199a*, -200a and -100 in ovarian cancers and their alterations are associated with high grade and late stage tumor. Significantly, miR-214 induces cell survival and cisplatin resistance through targeting 3′UTR of the PTEN, which leads to down regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3′UTR largely abrogates miR-214 induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.

1 . A method for treating ovarian cancer in a mammal comprising (i) obtaining a biological sample from the tumor or cancer; (ii) determining whether the tumor or cancer overexpresses an Akt kinase, (iii) if the tumor or cancer overexpresses Akt kinase, treating the tumor or cancer with an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower 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. 
       
     
     
         2 . The method of  claim 1 , wherein the subject has been diagnosed with ovarian cancer. 
     
     
         3 . The method of  claim 1 , wherein the level of Akt kinase expression is determined by assaying the cancer for the presence of a phosphorylated Akt kinase. 
     
     
         4 . The method of  claim 1 , wherein the level of Akt kinase expression is determined by assaying the cancer for the presence of a phosphorylated Akt kinase with an antibody. 
     
     
         5 . A method of treating a tumor or cancer in a mammal comprising administering to the mammal an effective amount of a compound of formula 
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower 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; 
         wherein the compound is administered one time per week for three weeks followed by a one week period wherein the compound is not administered. 
       
     
     
         6 . The method of  claim 5 , wherein the dosing schedule is repeated at least twice. 
     
     
         7 . The method of  claim 5 , wherein the dosing schedule is repeated at least 4 times. 
     
     
         8 . The method of  claim 5 , wherein the tumor is selected from the group consisting of breast, pancreatic, ovarian and colorectal tumors. 
     
     
         9 . The method of  claim 5 , wherein at least 10 mg/m 2  of the compound is administered. 
     
     
         10 . The method of  claim 5 , wherein 10 mg/m 2  or less of the compound is administered. 
     
     
         11 . A method to treat ovarian cancer in a mammal comprising administering to the mammal a dose of 10 mg/m 2  or less of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower 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; 
         wherein the compound is administered one time per week. 
       
     
     
         12 . The method of  claim 11 , wherein the dosing regimen is repeated for at least two weeks. 
     
     
         13 . The method of  claim 11 , wherein the dosing regiment is repeated for three weeks, and wherein the three week period is followed by a one week period wherein no drug is administered. 
     
     
         14 . The method of  claim 13 , wherein the dosing regimen represents a dosing cycle. 
     
     
         15 . The method of  claim 14 , wherein the dosing cycle is repeated at least twice. 
     
     
         16 . The method of  claim 14  wherein the dosing cycle is repeated until regression of the cancer is achieved. 
     
     
         17 . The method of  claim 1 ,  5  or  11 , wherein the drug is administered intravenously. 
     
     
         18 . The method of  claim 1 ,  5  or  11 , wherein the subject has been diagnosed with a carcinoma, sarcoma, lymphoma, leukemia, or myeloma. 
     
     
         19 . The method of  claim 1 ,  5 , or  11  wherein the mammal is a human. 
     
     
         20 . The method of  claim 1 ,  5  or  11 , wherein the compound is the compound of Formula IB: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 1 ,  5  or  11 , wherein the compound is the compound of Formula IIA: 
       
         
           
           
               
               
           
         
       
     
     
         22 . Use of a compound of the formula below to treat ovarian cancer which use includes (i) obtaining a biological sample from the tumor or cancer; (ii) determining whether the tumor or cancer overexpresses an Akt kinase, (iii) if the tumor or cancer overexpresses Akt kinase, treating the tumor or cancer with an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower 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. 
       
     
     
         23 . The use of  claim 22 , wherein the subject has been diagnosed with ovarian cancer. 
     
     
         24 . The use of  claim 22 , wherein the level of Akt kinase expression is determined by assaying the cancer for the presence of a phosphorylated Akt kinase. 
     
     
         25 . The use of  claim 22 , wherein the level of Akt kinase expression is determined by assaying the cancer for the presence of a phosphorylated Akt kinase with an antibody. 
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower 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; 
         wherein the compound is administered one time per week for three weeks followed by a one week period wherein the compound is not administered. 
       
     
     
         27 . The use of claim  26 , wherein the dosing schedule is repeated at least twice. 
     
     
         28 . The use of claim  26 , wherein the dosing schedule is repeated at least 4 times. 
     
     
         29 . The use of claim  26 , wherein the tumor is selected from the group consisting of breast, pancreatic, ovarian and colorectal tumors. 
     
     
         30 . The use of claim  26 , wherein at least 10 mg/m 2  of the compound is administered. 
     
     
         31 . The use of claim  26 , wherein 10 mg/m 2  or less of the compound is administered. 
     
     
         32 . Use of a compound of the formula below to treat ovarian cancer at a dose of 10 mg/m 2  or less 
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower 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; 
         wherein the compound is administered one time per week. 
       
     
     
         33 . The use of  claim 32 , wherein the dosing regimen is repeated for at least two weeks. 
     
     
         34 . The use of  claim 32 , wherein the dosing regiment is repeated for three weeks, and wherein the three week period is followed by a one week period wherein no drug is administered. 
     
     
         35 . The use of  claim 32 , wherein the dosing regimen represents a dosing cycle. 
     
     
         36 . The use of  claim 32 , wherein the dosing cycle is repeated at least twice. 
     
     
         37 . The use of  claim 36  wherein the dosing cycle is repeated until regression of the cancer is achieved. 
     
     
         38 . The use of claim  26 ,  32  or  36 , wherein the drug is administered intravenously. 
     
     
         39 . The use of claim  26 ,  32  or  36 , wherein the subject has been diagnosed with a carcinoma, sarcoma, lymphoma, leukemia, or myeloma. 
     
     
         40 . The use of claim  26 ,  32  or  36  wherein the mammal is a human. 
     
     
         41 . The use of claim  26 ,  32  or  36 , wherein the compound is the compound of Formula IB: 
       
         
           
           
               
               
           
         
       
     
     
         42 . The use of claim  26 ,  32  or  36 , wherein the compound is the compound of Formula IIA: