Compositions including triciribine and trastuzumab and methods of use thereof
This application relates to combination therapies including triciribine and related compounds and trastuzumab or a salt thereof and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.
1. A method for identifying and treating a subject having a tumor or cancer cell with enhanced sensitivity to triciribine (TCN) comprising:
(a) determining whether a patient has a tumor or cancer cell with enhanced sensitivity to triciribine or triciribine phosphate comprising:
(i) obtaining a biological sample of the tumor or cancer cell from the subject;
(ii) measuring the expression level of Akt kinase from the tumor or cancer cell from the subject; and
(iii) comparing the expression level of Akt kinase from the tumor or cancer cell to the expression level in a control tissue,
wherein a 1.5 fold greater expression of Akt in the tumor or cancer cell compared to a control tissue is indicative of a patient having a tumor or cancer cell with enhanced sensitivity to triciribine or triciribine phosphate; and
(b) administering to the patient having a tumor or cancer cell with enhanced sensitivity triciribine or triciribine phosphate:
(i) at least one triciribine compound of the formula:
wherein each R 2 ′, R 3 ′, and R 5 ′ are independently hydrogen, optionally substituted phosphate or phosphonate; acyl; alkyl; amide, sulfonate ester; sulfonyl, wherein the phenyl group is optionally substituted with halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; 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 ′, R 3 ′ or R 5 ′ 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, optionally substituted arylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group; and
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, or aralkylsulfonyl;
(ii) trastuzumab or a salt thereof; and
(iii) a pharmaceutically acceptable carrier, wherein said treatment comprises administering 45 mg/m 2 or less of at least one triciribine compound over a one-hour intravenous infusion on days 1, 8, and 15 every 28 days until regression of the tumor or cancer cell is evident.
2. The method of claim 1 , wherein the biological sample is taken from breast, pancreas, ovary, colon, or rectum.
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. The method of claim 1 , wherein the administration is repeated at least twice.
6. The method of claim 1 , wherein the administration is repeated at least 4 times.
7. The method of claim 1 , wherein at least 10 mg/m 2 of the triciribine compound is administered.
8. The method of claim 1 , wherein 10 mg/m 2 or less of the triciribine compound is administered.
9. The method of claim 1 , wherein the administration is repeated until regression of the cancer is achieved.
10. The method of claim 1 , wherein the subject has been diagnosed with a carcinoma, sarcoma, lymphoma, leukemia, or myeloma.
11. The method of claim 1 wherein the subject is mammal.
12. The method of claim 1 wherein the subject is human.
13. The method of claim 1 , wherein the triciribine compound is:
14. The method of claim 1 , wherein the triciribine compound is:
15. The method of claim 1 , wherein at least 100 mg of trastuzumab or a salt thereof is administered.
16. The method of claim 1 , wherein at least 200 mg of trastuzumab or a salt thereof is administered.
17. The method of claim 1 , wherein at least 400 mg of trastuzumab or a salt thereof is administered.