Targeting glioblastoma stem cells through the tlx-tet3 axis

Abstract

Methods and compositions capable of modulating activity of TLX (NR2E1), a nuclear receptor essential for neural stem cell self-renewal are provided. The modulation may comprise downregulating TLX expression and/or modulating TET3. In addition, methods of delivering shRNAs using dendrimer nanoparticles into glioblastoma stem cells are provided. The methods and compositions are useful for treating and preventing the progression of brain cancer, e.g., glioblastoma.

1 . A method of treating an individual suspected of having, having, or diagnosed with brain cancer, said method comprising administering an effective amount of a composition that upregulates expression of TET3. 
     
     
         2 . The method of  claim 1 , wherein the brain cancer is selected from the group consisting of glioblastoma, oligodendroglioma, dysembryoplastic neuroepithelial tumor, mesenchymal gliomas, pilocytic astrocytomas, neurocytoma, and ependymoma. 
     
     
         3 . The method of  claim 1 , wherein the composition that upregulates TET3 expression acts at a DNA level, an RNA level, or at a translational level. 
     
     
         4 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the composition that upregulates TET3 expression comprises a small molecule that binds to and occludes a TLX ligand binding site. 
     
     
         13 . The method of  claim 12 , wherein the small molecule comprises all-trans retinoic acid (ATRA). 
     
     
         14 - 32 . (canceled) 
     
     
         33 . A method of treating an individual suspected of, having, or diagnosed with brain cancer, said method comprising upregulating expression of TET3. 
     
     
         34 . The method of  claim 33 , wherein TET3 is upregulated by viral transduction of a TET3 expressing vector, episomal transfection of a TET3 expressing vector, transfection of TET3 mRNA, transfection of TET3 protein, or activation of the endogenous TET3 promoter of said subject. 
     
     
         35 . The method of  claim 33 , wherein TETs is upregulated by a gene editing method. 
     
     
         36 . The method of  claim 35 , wherein the gene editing method is Zinc finger nuclease, transcription activator-like effector-based nucleases/TALEN, CRISPR/Cas9, or engineered meganuclease. 
     
     
         37 . The method of  claim 33 , wherein the brain cancer is selected from the group consisting of glioblastoma, oligodendroglioma, dysembryoplastic neuroepithelial tumor, mesenchymal gliomas, pilocytic astrocytomas, neurocytoma, and ependymoma.