Methods and compositions for the treatment of cancer

Abstract

Some embodiments of the present invention relate to agents and compositions for treating cancer. More embodiments include agents and compositions for modulating the activity of the Hedgehog pathway.

1 .- 212 . (canceled) 
     
     
         213 . A method of inhibiting an increase in expression of a DNA repair gene in a cell contacted with a platinum-based chemotherapeutic compound comprising reducing the level of a nucleic acid encoding GLI1 or reducing the level of GLI1 protein in the cell. 
     
     
         214 . The method of  claim 213 , wherein the level of a nucleic acid encoding GLI1 or the level of GLI1 protein is reduced by contacting the cell with an isolated nucleic acid selected from a small hairpin RNA (shRNA), a small interfering RNA (siRNA), a micro RNA (miRNA), an antisense polynucleotide, and a ribozyme. 
     
     
         215 . The method of  claim 214 , wherein the isolated nucleic acid comprises a sequence encoding antisense GLI1 or a fragment thereof, or an antisense nucleic acid complementary to a sequence encoding GLI1 or a fragment thereof. 
     
     
         216 . The method of  claim 214 , wherein the isolated nucleic acid comprises a sequence selected from SEQ ID NOS:01-10. 
     
     
         217 . The method of  claim 213 , wherein the nucleic acid encoding GLI1 comprises a nucleic acid encoding GLI1-130, or the GLI1 protein comprises GLI1-130 isoform. 
     
     
         218 . The method of  claim 213 , wherein the DNA repair gene is selected from the group consisting of XRCC1, ERCC1 and XPD. 
     
     
         219 . The method of  claim 213 , wherein the cell's resistance to the platinum-based chemotherapeutic compound is decreased compared to a cell in which the level of a nucleic acid encoding GLI1 has not been reduced or in which the level of GLI1 protein has not been reduced. 
     
     
         220 . The method of  claim 219 , wherein the cell's resistance to the platinum-based chemotherapeutic compound is decreased at least about 6-fold. 
     
     
         221 . The method of  claim 213 , wherein the level of phosphorylated c-jun (Ser 63) protein in the cell in which the level of a nucleic acid encoding GLI1 has been reduced or in which the level of GLI1 protein has been reduced is reduced compared to a cell in which the level of a nucleic acid encoding GLI1 has not been reduced or the level of GLI1 protein has not been reduced. 
     
     
         222 . The method of  claim 213 , wherein the level of phosphorylated c-jun (Thr 91) protein in the cell in which the level of a nucleic acid encoding GLI1 has been reduced or in which the level of GLI1 protein has been reduced is increased compared to a cell in which the level of a nucleic acid encoding GLI1 has not been reduced or the level of GLI1 protein has not been reduced. 
     
     
         223 . The method of  claim 213 , wherein the platinum-based chemotherapeutic compound is selected from the group consisting of cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate. 
     
     
         224 . A method of reducing the level of repair of platinum-DNA adducts in a cell contacted with a platinum-based chemotherapeutic compound comprising reducing the level of a nucleic acid encoding GLI1 or reducing the level of GLI1 protein in the cell. 
     
     
         225 . The method of  claim 224 , wherein the level of a nucleic acid encoding GLI1 or the level of GLI1 protein is reduced by contacting the cell with an isolated nucleic acid selected from a small hairpin RNA (shRNA), a small interfering RNA (siRNA), a micro RNA (miRNA), an antisense polynucleotide, and a ribozyme. 
     
     
         226 . The method of  claim 225 , wherein the isolated nucleic acid comprises a sequence encoding antisense GLI1 or a fragment thereof, or an antisense nucleic acid complementary to a sequence encoding GLI1 or a fragment thereof. 
     
     
         227 . The method of  claim 225 , wherein the isolated nucleic acid comprises a sequence selected from SEQ ID NOS:01-10. 
     
     
         228 . The method of  claim 224 , wherein the nucleic acid encoding GLI1 comprises a nucleic acid encoding GLI1-130, or the GLI1 protein comprises GLI1-130 isoform. 
     
     
         229 . The method of  claim 224 , wherein the reduction in the level of repair of platinum-DNA adducts in the cell having a reduced level of a nucleic acid encoding GLI1 or a reduced level of GLI1 protein compared to the level of repair of platinum-DNA adducts in a cell contacted with a platinum-based chemotherapeutic compound and in which the level of a nucleic acid encoding GLI1 has not been reduced or in which the level of GLI1 protein has not been reduced is greater than about 60%. 
     
     
         230 . The method of  claim 224 , wherein the cell's resistance to the platinum-based chemotherapeutic compound is decreased compared to a cell in which the level of a nucleic acid encoding GLI1 has not been reduced or in which the level of GLI1 protein has not been reduced. 
     
     
         231 . The method of  claim 230 , wherein the cell's resistance to the platinum-based chemotherapeutic compound is decreased at least about 6-fold. 
     
     
         232 . The method of  claim 224 , wherein the level of phosphorylated c-jun (Ser 63) protein in the cell in which the level of a nucleic acid encoding GLI1 has been reduced or in the level of GLI1 protein has been reduced is reduced compared to a cell in which the level of a nucleic acid encoding GLI1 has not been reduced or in which the level of GLI1 protein has not been reduced. 
     
     
         233 . The method of  claim 224 , wherein the level of phosphorylated c-jun (Thr 91) protein in the cell in which the level of a nucleic acid encoding GLI1 has been reduced or in the level of GLI1 protein has been reduced is increased compared to a cell in which the level of a nucleic acid encoding GLI1 has not been reduced or in which the level of GLI1 protein has not been reduced. 
     
     
         234 . The method of  claim 224 , wherein the platinum-based chemotherapeutic compound is selected from the group consisting of cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.