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, which may be associated with KRAS mutation in a mammal in need thereof, by 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 malignant tumor, the composition comprising RNAi molecules and pharmaceutically acceptable excipients, wherein the RNAi molecules comprise a sense strand which comprises  CCU UU U GAGA C C CU GC U GU UU  (SEQ ID NO:294) and an antisense strand which comprises ACAgCaGgGUCUCAAAAGG UU  (SEQ ID NO:298), or wherein the RNAi molecules comprise a sense strand which comprises  GG A U GAC U A U G U GAAGG C A UU  (SEQ ID NO:303) and an antisense strand which comprises UGCcUuCaCAUAGUCAUCC UU  (SEQ ID NO:305), wherein an uppercase letter refers to an unmodified ribonucleotide, wherein a lower case letter refers to 2′-deoxy, and wherein the underlined nucleotides are 2′-OMe-substituted. 
     
     
         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;   wherein the RNAi molecules comprise a sense strand which comprises  CCU UU U GAGA C C CU GC U GU UU  (SEQ ID NO:294) and an antisense strand which comprises ACAgCaGgGUCUCAAAAGG UU  (SEQ ID NO:298), or wherein the RNAi molecules comprise a sense strand which comprises  GG A U GAC U A U G U GAAGG C A UU  (SEQ ID NO:303) and an antisense strand which comprises UGCcUuCaCAUAGUCAUCC UU  (SEQ ID NO:305), wherein an uppercase letter refers to an unmodified ribonucleotide, wherein a lower case letter refers to 2′-deoxy, and wherein the underlined nucleotides are 2′-OMe-substituted.   
     
     
         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 administration 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 method reduces one or more symptoms of the malignant tumor, or delays or terminates the progression of the malignant tumor. 
     
     
         12 . The method of  claim 6 , wherein the administration reduces growth of malignant tumor cells in the subject. 
     
     
         13 . The method of  claim 6 , wherein the administration reduces growth for at least 10% of the malignant tumor cells in the subject. 
     
     
         14 . 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. 
     
     
         15 . The method of  claim 6 , wherein the tumor cell over-expresses wild-type GST-π RNA or protein. 
     
     
         16 . 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. 
     
     
         17 . 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. 
     
     
         18 . 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. 
     
     
         19 . 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. 
     
     
         20 . 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. 
     
     
         21 . An RNAi molecule comprising a sense strand which comprises  CCU UU U GAGA C C CU GC U GU UU  (SEQ ID NO:294) and an antisense strand which comprises ACAgCaGgGUCUCAAAAGG UU  (SEQ ID NO:298), wherein an uppercase letter refers to an unmodified ribonucleotide, wherein a lower case letter refers to 2′-deoxy, and wherein the underlined nucleotides are 2′-OMe-substituted. 
     
     
         22 . An RNAi molecule comprising a sense strand which comprises  GG A U GAC U A U G U GAAGG C A UU  (SEQ ID NO:303) and an antisense strand which comprises UGCcUuCaCAUAGUCAUCC UU  (SEQ ID NO:305), wherein an uppercase letter refers to an unmodified ribonucleotide, wherein a lower case letter refers to 2′-deoxy, and wherein the underlined nucleotides are 2′-OMe-substituted.