COMPOUNDS THAT TARGET MYC microRNA RESPONSIVE ELEMENTS FOR THE TREATMENT OF MYC-ASSOCIATED CANCER

Abstract

Novel mIR-330 agents and their methods of use are provided. Methods of treating MYC-associated cancers are provided.

1 . A method of treating a MYC-associated cancer in a subject in need thereof, the method comprising:
 selecting a subject that overexpresses MYC; and   administering to the subject a pharmaceutical composition comprising a nucleic acid sequence having at least 80% complementarity to a micro RNA (miR) Responsive Element (MRE) sequence set forth as SEQ ID NO:1, thereby treating cancer in the subject.   
     
     
         2 . The method of  claim 1 , wherein the nucleic acid sequence has at least 90% complementarity, 95% complementarity, or 98% complementarity to the MRE sequence set forth as SEQ ID NO:1. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the nucleic acid sequence is further perfectly complementary to an MRE seed sequence set forth as SEQ ID NO:2. 
     
     
         6 . The method of  claim 1 , wherein the nucleic acid sequence comprises a miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 6 , wherein the miRNA or siRNA is between 20 and 24 nucleotides in length. 
     
     
         9 . The method of  claim 1 , wherein the MYC-associated cancer is further characterized by downregulation of hsa-miR-330-5p. 
     
     
         10 . The method of  claim 1 , wherein the MRE is a MYC MRE. 
     
     
         11 . The method of  claim 1 , wherein MYC expression is downregulated in the subject after administering the pharmaceutical composition to the subject. 
     
     
         12 . The method of  claim 1 , wherein MYC mRNA cleavage is mediated or translation of MYC mRNA is inhibited. 
     
     
         13 . The method of  claim 1 , wherein the MYC-associated cancer is liver cancer or colorectal cancer. 
     
     
         14 . The method of  claim 1 , wherein the nucleic acid sequence is administered using a recombinant Adeno-Associated virus (AAV). 
     
     
         15 . The method of  claim 1 , wherein the nucleic acid sequence is a double-stranded nucleic acid sequence having a sense strand and an antisense strand, wherein the antisense strand has at least 80% complementarity to the MRE sequence. 
     
     
         16 . A method of targeting MYC overexpression in a cancer cell characterized by overexpression of MYC, comprising contacting the cell with [[a]] the nucleic acid sequence of  claim 1  to inhibit translation of the MYC mRNA. 
     
     
         17 . The method of  claim 16 , wherein the nucleic acid sequence comprises a miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound. 
     
     
         18 . (canceled) 
     
     
         19 . An isolated nucleic acid comprising a sequence between 20 and 24 nucleotides in length having at least 80% complementarity to an MRE sequence set forth as SEQ ID NO:1 and comprising a modified nucleotide. 
     
     
         20 . The isolated nucleic acid sequence of  claim 19 , wherein the isolated nucleic acid sequence is further perfectly complementary to an MRE seed sequence set forth as SEQ ID NO:2. 
     
     
         21 . The isolated nucleic acid sequence of  claim 20 , having at least 90% complementarity, 95% complementarity, or 98% complementarity to the MRE sequence set forth as SEQ ID NO:1. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The isolated nucleic acid sequence of  claim 19 , comprising an miRNA or an siRNA, optionally wherein the miRNA is a miR-330-5p compound. 
     
     
         25 . (canceled) 
     
     
         26 . A method of treating a MYC-associated cancer in a subject in need thereof, the method comprising:
 selecting a subject that overexpresses MYC; and   administering to the subject a pharmaceutical composition comprising a modified miR-330 compound and/or a miR-330 analogue compound comprising SEQ ID NO:3, thereby treating cancer in the subject.   
     
     
         27 . (canceled) 
     
     
         28 . An isolated nucleic acid comprising a sequence between 20 and 24 nucleotides in length comprising at least 90% identity to SEQ ID NO:3, and comprising a modified nucleotide, wherein said nucleic acid sequence directs cleavage of MYC mRNA or inhibits translation of MYC mRNA. 
     
     
         29 . The isolated nucleic acid sequence of  claim 28 , comprising at least 95% identity to SEQ ID NO:3. 
     
     
         30 . The isolated nucleic acid sequence of  claim 28 , comprising SEQ ID NO:3. 
     
     
         31 . A miR-330-5p analogue comprising a nucleic acid sequence comprising at least 90% identity to SEQ ID NO:3, and having at least one modification selected from the group consisting of a deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, an amino-modified nucleotide, an alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate-modified nucleotide, a non-natural base-comprising nucleotide, an O-methyl modified nucleotide and a phosphorothioate. 
     
     
         32 . The miR-330-5p analogue of  claim 31 , comprising at least 95% identity to SEQ ID NO:3. 
     
     
         33 . The miR-330-5p analogue of  claim 31 , wherein said miR-330-5p analogue inhibits translation of MYC mRNA.