Methods and Compositions Related To miR-21 and miR-29A, Exosome Inhibition And Cancer Metastasis

Abstract

The present invention provides materials and methods related to the discovery that tumor secreted miR-21 and miR-29a can function by binding as ligands to receptors of the Toll-like receptor family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response, which leads to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is important in the tumor-immune system communication, in tumor growth and spread, and in cancer treatment.

What is claimed is: 
     
         1 . A composition of matter comprising at least one anti-miR-21 inhibitor and at least acid anti-miR-29a inhibitor in at least one pharmaceutically-acceptable carrier or excipient. 
     
     
         2 . The composition of  claim 1 , wherein the anti-miR-21 inhibitor comprises at least one locked nucleic acid anti-miR-21 inhibitor, and the anti-miR-29a inhibitor comprises at least one locked nucleic acid anti-miR-29a inhibitor. 
     
     
         3 . The composition of  claim 1 , which further comprises an additional chemotherapeutic compound. 
     
     
         4 . A composition of matter, comprising at least one exosome inhibitor selected from the group consisting of: an antisense miR-21 exosome inhibitor, and an antisense miR-29a exosome inhibitor. 
     
     
         5 . The composition of  claim 4 , where in the antisense miR-21 exosome inhibitor comprises a locked nucleic acid anti-miR-21 exosome inhibitor. 
     
     
         6 . The composition of  claim 4 , wherein the antisense miR-29a exosome inhibitor comprises a locked nucleic acid anti-miR-29a exosome inhibitor. 
     
     
         7 . The composition of  claim 4 , wherein the antisense miR-21 exosome inhibitor comprises an antisense miR-21 having a modification in a GU motif in the nucleotide region 18-21 of miR-21 sequence. 
     
     
         8 . The composition of  claim 7 , wherein the modification in the GU motifs comprises substituting one or more bases at base numbers 18 and 20 in the miR-21 sequence. 
     
     
         9 . The composition of  claim 7 , wherein the modification comprises GUUG. 
     
     
         10 . The composition of  claim 4 , wherein the antisense miR-29a exosome inhibitor comprises an antisense miR-29a having a modification in a GU motif in the nucleotide region 18-21 of miR-29a sequence. 
     
     
         11 . The composition of  claim 10 , wherein the modification in the GU motifs comprises substituting one or more bases at base numbers 20 and 21 in the miR-21 sequence. 
     
     
         12 . The method of  claim 11 , wherein the modification comprises GGUU.