Agents and methods for treating pancreatic ductal adenocarcinomas

Abstract

It has been discovered that NAD+-dependent histone deacetylase SIRT6 is critical for suppression of PDAC by controlling the expression of Lin28b, which is a negative regulator of let-7 microRNA. Specifically, SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This invention relates generally to agents and methods of reducing expression or activity of Lin28b to treat (aggressive) PDAC in a subject.

1 .- 22 . (canceled) 
     
     
         23 . An inhibitory nucleic acid comprising a sequence of 5′-GCCTTGAGTCAATACGGGTAA-3′ (SEQ ID NO:3), with one or more modifications selected from a modified sugar moiety, a modified internucleoside linkage, a modified nucleotide, and combinations thereof. 
     
     
         24 . The inhibitory nucleic acid of  claim 23 , which is a small interfering RNA (siRNA), a short hairpin RNA (shRNA), LNA molecule, PNA molecule, or ribozyme. 
     
     
         25 . The inhibitory nucleic acid of  claim 23 , which is single-stranded. 
     
     
         26 . The inhibitory nucleic acid of  claim 23 , which is double-stranded. 
     
     
         27 . The inhibitory nucleic acid of  claim 26 , which is double-stranded and comprises an overhang at one or both termini. 
     
     
         28 . An inhibitory nucleic acid comprising a sequence that is at least 90% identical to 5′-GCCTTGAGTCAATACGGGTAA-3′ (SEQ ID NO:3), and that binds to and reduces expression of Lin28b. 
     
     
         29 . The inhibitory nucleic acid of  claim 28 , with one or more modifications selected from a modified sugar moiety, a modified internucleoside linkage, a modified nucleotide, and combinations thereof. 
     
     
         30 . The inhibitory nucleic acid of  claim 28 , which is a small interfering RNA (siRNA), a short hairpin RNA (shRNA), LNA molecule, PNA molecule, or ribozyme. 
     
     
         31 . The inhibitory nucleic acid of  claim 28 , which is single-stranded. 
     
     
         32 . The inhibitory nucleic acid of  claim 28 , which is double-stranded. 
     
     
         33 . The inhibitory nucleic acid of  claim 32 , which is double-stranded and comprises an overhang at one or both termini. 
     
     
         34 . A method of treating PDAC in a subject, the method comprising administering to the subject a therapeutically effective amount of the inhibitory nucleic acid of  claim 23  to specifically reduce expression of Lin28b, thereby treating PDAC in the subject. 
     
     
         35 . The method of  claim 34 , wherein the subject is a mammal. 
     
     
         36 . The method of  claim 34 , wherein the subject is a human. 
     
     
         37 . A method of treating PDAC in a subject, the method comprising administering to the subject a therapeutically effective amount of the inhibitory nucleic acid of claim  283  to specifically reduce expression of Lin28b, thereby treating PDAC in the subject. 
     
     
         38 . The method of  claim 37 , wherein the subject is a mammal. 
     
     
         39 . The method of  claim 37 , wherein the subject is a human.