Reagents and Methods for Treating Cancer

Abstract

This invention describes a genetic system for targeting the EVI1 gene in mammalian cells. The EVI1 gene is an oncogenic transcription factor that, when expressed, accelerates cell division and inhibits death of cells. Nucleotide sequences that block the expression of EVI1 and drug delivery systems for them are described. These nucleotide sequences cause a block in cell growth and division and trigger death of mammalian cells, including lung and ovarian cancer cells.

1 . A pharmaceutical composition for specifically reducing expression of the human Ecotropic Virus Integration site 1 (EVI1) gene in a tumor cell, the pharmaceutical composition comprising:
 an isolated polynucleotide comprising a sequence that is a contiguous portion of nucleotide sequence of SEQ ID NO: 1, wherein said contiguous portion of the nucleotide sequence of SEQ ID NO: 1 is from nucleotide 969 through 1002, and comprises a length of 19 to 30 nucleotides,   the pharmaceutical composition further comprising a chemotherapeutic drug or agent; and   a pharmaceutically acceptable carrier, excipient or adjuvant.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the isolated polynucleotide is an oligoribonucleotide comprising a RNA sequence that hybridizes to mRNA transcribed from said contiguous portion of the nucleotide sequence of SEQ ID NO: 1. 
     
     
         3 . The isolated double-stranded oligoribonucleotide, or shRNA or siRNA species thereof according to  claim 1 , wherein the oligoribonucleotide targets a nucleotide sequence of SEQ ID NO: 3. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the isolated polynucleotide is double-stranded, and wherein the isolated polynucleotide comprises a combination of SEQ ID NOS: 9 and 10. 
     
     
         5 . A method for inhibiting Ecotropic Virus Integration site 1 (EVI1) in a tumor cell, comprising the step of contacting a tumor cell with an effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         6 . The method of  claim 5  wherein the tumor cell is from:
 a tumor of lung, breast, prostate, or ovarian tissue or organ, or 
 a melanoma, or 
 acute myelocytic leukemia. 
 
     
     
         7 . The pharmaceutical composition of  claim 1 , further comprising a liposome. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the composition is encapsulated in a liposome. 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the liposome is PEGylated. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the liposome comprises a cell-targeting moiety. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the cell-targeting moiety is a protein, a peptide or an aptamer. 
     
     
         12 . The pharmaceutical composition of  claim 1 , further comprising a nanoparticle. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the composition is encapsulated in a nanoparticle. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein the nanoparticle comprises lipids, cyclodextrin, chitosan, carbohydrate polymers, elastin-like polymers (ELP), calcium phosphate polymers or combinations thereof. 
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein the nanoparticle is PEGylated. 
     
     
         16 . The pharmaceutical composition of  claim 12 , wherein the nanoparticle comprises a cell-targeting moiety. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the cell-targeting moiety is a protein, a peptide or an aptamer.