CANCER THERAPY USING Bcl-XL-SPECIFIC siNA

Abstract

The invention relates to a double-stranded short interfering nucleic acid (siNA) molecule specific to the Bcl-X L transcript, comprising a sense and an antisense region, wherein the sense region comprises the nucleotide sequence SEQ ID NO: 1 or a sequence having at least 70% identity, preferably at least 80% identity, more preferably at least 90% identity with said sequence, and the antisense region comprises a nucleotide sequence that is complementary to the sense region, and its use for treating cancer.

1 . A method of treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective dose of a pharmaceutical composition, wherein the pharmaceutical composition comprises an acceptable carrier and at least:
 a double-stranded short interfering nucleic acid molecule specific to the Bcl-XL transcript (Bcl-XL siNA) comprising a sense and an antisense region, wherein the sense region comprises the nucleotide sequence SEQ ID NO: 1 or a sequence having at least 70% identity with said sequence, and the antisense region comprises a nucleotide sequence that is complementary to the sense region, and wherein each strand comprises 15 to about 30 nucleotides, and each strand comprises 15 to about 30 nucleotides that are complementary to the nucleotides of the other strand; and   a short interfering nucleic acid molecule targeting the Mcl-1 transcript (Mcl-1 siNA).   
     
     
         2 . The method according to  claim 1 , wherein said cancer is selected from the group consisting of: ovarian, nasopharyngeal, breast, prostate and colon carcinoma, glioma, mesothelioma, and melanoma. 
     
     
         3 . The method according to  claim 1 , wherein said cancer is ovarian cancer. 
     
     
         4 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA comprises a 19- to 21-nucleotide duplex. 
     
     
         5 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA comprises ribonucleotides. 
     
     
         6 . The method according to  claim 1 , wherein the sense region of said Bcl-XL siNA comprises the nucleotide sequence SEQ ID NO: 1 and the antisense region of said Bcl-XL siNA comprises the nucleotide sequence SEQ ID NO: 4. 
     
     
         7 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA comprises 1 to about 3 overhanging nucleotides at the 3′ end of each strand. 
     
     
         8 . The method according to  claim 7 , wherein said Bcl-XL siNA consists of a sense strand of the sequence SEQ ID NO: 5 and an antisense strand of the sequence SEQ ID NO: 6. 
     
     
         9 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA comprises blunt end(s). 
     
     
         10 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA is assembled from two separate oligonucleotide fragments, wherein one fragment comprises the sense region and the second fragment comprises the antisense region of the siNA. 
     
     
         11 . The method according to  claim 1 , wherein the sense region of said Bcl-XL siNA and/or said Mcl-1 siNA is connected to the antisense region via a linker molecule. 
     
     
         12 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA comprises one or more modified pyrimidine and/or purine nucleotides. 
     
     
         13 . The method according to  claim 1 , wherein the strand of said Bcl-XL siNA and/or said Mcl-1 siNA comprising the sense region includes a terminal cap moiety at the 5′ and/or 3′-end(s). 
     
     
         14 . The method according to  claim 1 , wherein the strand of said Bcl-XL siNA and/or said Mcl-1 siNA comprising said antisense region includes a phosphate group at the 5′-end. 
     
     
         15 . The method according to  claim 1 , wherein said Bcl-XL siNA and/or said Mcl-1 siNA comprises at least one modified internucleotidic linkage. 
     
     
         16 . The method according to  claim 1 , wherein the pharmaceutical composition further comprises at least one anticancer drug. 
     
     
         17 . The method according to  claim 16 , wherein the anticancer drug is selected from the group consisting of: cytotoxic agents, anti-angiogenic factors, tyrosine kinase inhibitors and BH3 mimetics. 
     
     
         18 . The method according to  claim 16 , wherein the anticancer drug is a cytotoxic agent. 
     
     
         19 . The method according to  claim 1 , wherein the sense region of the short interfering nucleic acid molecule specific to the Bcl-XL transcript has at least 80% identity with said sequence SEQ ID NO: 1. 
     
     
         20 . The method according to  claim 1 , wherein the sense region of the short interfering nucleic acid molecule specific to the Bcl-XL transcript has at least 90% identity with said sequence SEQ ID NO: 1.