Methods and compositions for treating malignant tumors associated with KRAS mutation

Abstract

This invention provides methods and compositions for preventing, treating or ameliorating one or more symptoms of a malignant tumor associated with KRAS mutation in a mammal in need thereof, by identifying a tumor cell in the mammal, the tumor cell comprising at least one of: (i) a mutation of the KRAS gene, and (ii) an aberrant expression level of KRAS protein; and administering to the mammal a therapeutically effective amount of a composition comprising one or more RNAi molecules that are active in reducing expression of GST-π.

What is claimed is: 
     
       1. A pharmaceutical composition for the treatment or therapy of a tumor associated with a mutation in the KRAS gene or overexpression of wild-type KRAS gene, the composition comprising RNAi molecules and pharmaceutically acceptable excipients, wherein the RNAi molecules comprise an antisense strand which comprises SEQ ID NO: 184 and a sense strand which comprises SEQ ID NO: 158. 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the RNAi molecules are siRNAs or shRNAs. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipients include one or more lipid compounds. 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipients include lipid nanoparticles. 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipients include lipid nanoparticles that encapsulate the RNAi molecules. 
     
     
       6. A method for preventing, treating or ameliorating one or more symptoms of a malignant tumor associated with KRAS mutation in a mammal in need thereof, the method comprising:
 identifying a tumor cell in the mammal, the tumor cell comprising at least one of: (i) a mutation of the KRAS gene, and (ii) an aberrant expression level of KRAS protein; and 
 administering to the mammal a therapeutically effective amount of a composition comprising one or more RNAi molecules that are active in reducing expression of GST-π, and wherein the RNAi molecules comprise an antisense strand which comprises SEQ ID NO: 184 and a sense strand which comprises SEQ ID NO: 18. 
 
     
     
       7. The method of  claim 6 , wherein the mammal is a human and the GST-π is a human GST-π. 
     
     
       8. The method of  claim 6 , wherein the RNAi molecule is a siRNA or shRNA. 
     
     
       9. The method of  claim 6 , wherein the RNAi molecule decreases expression of GST-π in the mammal. 
     
     
       10. The method of  claim 6 , wherein the administration decreases expression of GST-π in the mammal by at least 5% for at least 5 days. 
     
     
       11. The method of  claim 6 , wherein the administration decreases the volume of the malignant tumor in the mammal by at least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%. 
     
     
       12. The method of  claim 6 , wherein the method reduces one or more symptoms of the malignant tumor, or delays or terminates the progression of the malignant tumor. 
     
     
       13. The method of  claim 6 , wherein the administration reduces growth of malignant tumor cells in the subject. 
     
     
       14. The method of  claim 6 , wherein the administration reduces growth for at least 2%, or at least 5%, or at least 10%, or at least 15%, or at least 20% of the malignant tumor cells in the subject. 
     
     
       15. The method of  claim 6 , wherein the tumor cells comprise increased levels of expression of wild type KRAS protein compared to that in a normal cell. 
     
     
       16. The method of  claim 6 , wherein the tumor cell over-expresses wild-type GST-π RNA or protein. 
     
     
       17. The method of  claim 6 , wherein the tumor cell comprises mutations in the KRAS protein at one or more of residues 12, 13 and 61. 
     
     
       18. The method of  claim 6 , wherein the tumor cell comprises mutations in the KRAS protein and the tumor is a cancer selected from lung cancer, colon cancer, and pancreatic cancer. 
     
     
       19. The method of  claim 6 , wherein the tumor cell comprises mutations in the KRAS protein and the tumor is a sarcoma or carcinoma selected from the group consisting of lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma. 
     
     
       20. The method of  claim 6 , wherein the malignant tumor is a sarcoma or carcinoma selected from the group of lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, colorectal carcinoma, breast cancer, and fibrosarcoma. 
     
     
       21. The method of  claim 6 , wherein the malignant tumor is located in an anatomical region selected from the group of lung, colon, pancreas, gallbladder, liver, breast, and any combination thereof. 
     
     
       22. The method of  claim 6 , wherein the administration is performed from 1 to 12 times per day. 
     
     
       23. The method of  claim 6 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6 or 7 days. 
     
     
       24. The method of  claim 6 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6, 8, 10 or 12 weeks. 
     
     
       25. The method of  claim 6 , wherein the administration is a dose of from 0.01 to 2 mg/kg of the RNAi molecules at least once per day for a period up to twelve weeks. 
     
     
       26. The method of  claim 6 , wherein the administration provides a mean AUC(0-last) of from 1 to 1000 ug*min/mL and a mean C max  of from 0.1 to 50 ug/mL for the GST-π RNAi molecule. 
     
     
       27. The method of  claim 6 , wherein the administration is intravenous injection, intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, oral, topical, infusion, or inhalation.