Mir-211 expression and related pathways in human melanoma

Abstract

Provided herein are methods for the diagnosis of resistance to chemotherapeutic agents by assessing the regulatory pathways of PGC1α. Methods for treating drug-resistant melanoma are also provided.

What is claimed is: 
     
         1 . A method for diagnosing vemurafenib resistance in a subject suffering from melanoma comprising:
 (i) assessing the expression level of PGC1α in a biological sample obtained from the subject;   (ii) comparing the expression level of PGC1α in the sample to the a reference expression level derived from the expression level of PGC1α in samples obtained from cells having vemurafenib-sensitivity; and   (iii) identifying the subject as having a vemurafenib-resistant phenotype when the expression level of PGC1α in the sample is less than the reference expression level or identifying the subject having a vemurafenib-sensitive phenotype when the expression level of PGC1α in the sample is not less than the reference expression level.   
     
     
         2 . The method of  claim 1 , wherein the biological sample comprises skin. 
     
     
         3 . The method of  claim 1 , wherein the biological sample comprises skin epidermis. 
     
     
         4 . The method of  claim 1 , wherein the biological sample comprises melanocytes. 
     
     
         5 . The method of  claim 1 , wherein the expression level of PGC1α is assessed by evaluating the amount of PGC1 mRNA in the biological sample. 
     
     
         6 . The method of  claim 5 , wherein evaluating the PGC1αmRNA comprises reverse transcriptase PCR (RT-PCR). 
     
     
         7 . The method of  claim 5 , wherein evaluating the PGC1α mRNA comprises array hybridization, wherein the array comprises an immobilized nucleic acid probe that specifically hybridizes PGC1α mRNA, PGC1α cDNA, or complements thereof. 
     
     
         8 . A method of treating melanoma in a subject suffering from melanoma, said method comprising:
 administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one agent that acts to decrease the biological activity of PGC1α.   
     
     
         9 . The method  claim 8 , wherein the therapeutic agent comprises a nucleic acid encoding an shPGC1α or siPGC1α. 
     
     
         10 . The method of  claim 9 , wherein the nucleic acid is encoded in a vector. 
     
     
         11 . The method of  claim 9 , wherein the vector is a viral vector. 
     
     
         12 . The method of  claim 9 , wherein the therapeutic agent is contained within a liposome. 
     
     
         13 . The method of  claim 9 , wherein the therapeutic agent further acts to increase the biological activity of miR-211. 
     
     
         14 . The method of  claim 9 , wherein the biological activity is increased by 10% or greater, 
     
     
         15 . The method of  claim 9 , wherein the biological activity is increased by 50% or greater. 
     
     
         16 . The method of  claim 9 , wherein the biological activity is increased by 100% or greater. 
     
     
         17 . A method of treating melanoma in a patient suffering from melanoma, said method comprising:
 administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one agent that acts to decrease the biological activity of IGFBP5.   
     
     
         18 . The method  claim 17 , wherein the therapeutic agent comprises a nucleic acid encoding an shIGFBP5 or siIGFBP5. 
     
     
         19 . The method of  claim 18 , wherein the nucleic acid is encoded in a vector. 
     
     
         20 . The method of  claim 18 , wherein the vector is a viral vector. 
     
     
         21 . The method of  claim 17 , wherein the therapeutic agent is contained within a liposome. 
     
     
         22 . A method of treating melanoma in a patient suffering from melanoma, said method comprising:
 administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one agent that acts to decrease the biological activity of PDK4.   
     
     
         23 . The method  claim 22 , wherein the therapeutic agent comprises a nucleic acid encoding an shPDK4 or siPDK4. 
     
     
         24 . The method of  claim 23  wherein the nucleic acid is encoded in a vector. 
     
     
         25 . . The method of  claim 23 , wherein the vector is a viral vector. 
     
     
         26 . The method of  claim 22 , wherein the therapeutic agent is contained within a liposome.