TARGETED SENSITIZATION OF NON-DEL(5q) MALIGNANT CELLS

Abstract

Disclosed are molecules for treating non-del(5q) MDS that mimic allelic deficiency in de15q MDS to sensitize the malignant clones of patient without del(5q). The disclosed molecule contains an inhibitor of Cdc25C, an inhibitor of PP2Acα, or a combination thereof, and a toll like receptor-9 (TLR9) targeting ligand. The molecule can also contain lenalidomide, or an analogue or derivative thereof. Also disclosed is a composition comprising the disclosed molecule in a pharmaceutically acceptable carrier. Also disclosed is a method for treating non-del(5q) myelodysplastic syndrome (MDS) in a subject by administering to the subject a therapeutically effective amount of the disclosed pharmaceutical composition.

What is claimed is: 
     
         1 . A molecule comprising
 an oligonucleotide inhibitor of Cdc25C that directly inhibits gene expression of Cdc25C, an oligonucleotide inhibitor of PP2Acα that directly inhibits gene expression of PP2Acα, or a combination thereof;   a toll like receptor-9 (TLR9) targeting ligand; and   lenalidomide, or an synthetic lethal analogue thereof.   
     
     
         2 . The molecule of  claim 1 , comprising the oligonucleotide inhibitor of Cdc25C coupled to the oligonucleotide inhibitor of PP2Acα by a bivalent linker. 
     
     
         3 . The molecule of  claim 1 , wherein the TLR9 targeting ligand is coupled to the oligonucleotide inhibitor of Cdc25C or the oligonucleotide inhibitor of PP2Acα by a bivalent linker. 
     
     
         4 . The molecule of  claim 1 , wherein the lenalidomide is coupled to the oligonucleotide inhibitor of Cdc25C or the oligonucleotide inhibitor of PP2Acα by a bivalent linker. 
     
     
         5 . The molecule of  claim 1 , wherein the molecule is defined by the formula:
   TTL--IC--IP--LEN, or     TTL--IP--IC--LEN,   wherein “TTL” represents a TLR9 targeting ligand,   wherein “IC” represents an siRNA inhibitor of Cdc25C,   wherein “IP ” represents an-siRNA inhibitor of PP2Acα,   wherein “LEN” represents an lenalidomide, and   wherein “--” represents a bivalent linker.   
     
     
         6 . The molecule of  claim 1 , wherein the TLR9 targeting ligand is an unmethylated CpG oligodeoxynucleotide. 
     
     
         7 . The molecule of  claim 1 , wherein the oligonucleotide inhibitor of Cdc25C is an siRNA. 
     
     
         8 . The molecule of  claim 1 , wherein the oligonucleotide inhibitor of Cdc25C comprises the nucleic acid sequence SEQ ID NO:1, or a nucleic acid sequence having at least 80% sequence identity to SEQ ID NO:1. 
     
     
         9 . The molecule of  claim 1 , wherein the oligonucleotide inhibitor of PP2Acα is an siRNA. 
     
     
         10 . The molecule of  claim 1 , wherein the oligonucleotide inhibitor of PP2Acα comprises the nucleic acid sequence SEQ ID NO:2, or a nucleic acid sequence having at least 80% sequence identity to SEQ ID NO:2. 
     
     
         11 . A pharmaceutical composition comprising the molecule of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         12 . A method for treating non-del(5q) myelodysplastic syndrome (MDS) in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 11 .