Compositions and Methods for Treating Glioblastoma GBM

Abstract

Methods of treating a malignant glioma in a subject are disclosed. The methods comprise administering to the subject a therapeutically effective amount of a viral vector comprising: (i) a first polynucleotide sequence encoding a Fas-chimera (Fas-c), said first polynucleotide sequence comprising SEQ ID NOs: 2 and 3; and (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . A method of treating a malignant glioma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a viral vector comprising:
 (i) a first polynucleotide sequence encoding a Fas-chimera (Fas c); and   (ii) a second polynucleotide sequence encoding an endothelial cell-specific promoter or a periendothelial cell-specific promoter, thereby treating the malignant glioma.   
     
     
         4 . The method of  claim 3 , wherein said promoter is the sequence set forth in SEQ ID NO: 12. 
     
     
         5 . The method of  claim 3 , wherein said promoter is the sequence set forth in SEQ ID NO: 13. 
     
     
         6 . The method of  claim 3 , wherein the viral vector is an adenoviral vector. 
     
     
         7 . The method of  claim 6 , wherein said adenoviral vector is a non-replicating adenoviral vector. 
     
     
         8 . The method of  claim 3 , wherein said promoter comprises at least one copy of the sequence set forth in SEQ ID NO: 6, or the complementary sequence thereof. 
     
     
         9 . The method of  claim 8 , wherein said promoter comprises at least two copies of the sequence set forth in SEQ ID NO: 6, or the complementary sequence thereof. 
     
     
         10 . The method of  claim 8 , wherein said promoter comprises the sequence set forth in SEQ ID NO: 8, or the complementary sequence thereof. 
     
     
         11 . The method of  claim 8 , wherein said promoter comprises the sequence set forth in SEQ ID NO: 7, or the complementary sequence thereof. 
     
     
         12 . The method of  claim 3 , wherein said promoter comprises the hypoxia response element (HRE) set forth in SEQ ID NO: 5. 
     
     
         13 . The method of  claim 3 , wherein the viral vector consists of the sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 10. 
     
     
         14 . The method of  claim 3 , wherein the malignant glioma is selected from the group consisting of glioblastoma, astrocytoma, oligodendroglioma, ependymoma, and juvenile pilocystic astrocytoma. 
     
     
         15 . The method of  claim 3 , wherein the therapeutically effective amount of said viral vector is about 10 3  to about 10 16  virus particles. 
     
     
         16 . The method of  claim 15 , wherein the therapeutically effective amount of said viral vector is about 10 5  to about 10 13  virus particles. 
     
     
         17 . The method of  claim 15 , wherein the therapeutically effective amount of said viral vector is about 10 7  to about 10 12  virus particles. 
     
     
         18 . The method of  claim 15 , wherein the therapeutically effective amount of said viral vector is about 1_× — 10 12  to about 5× — 10 12  virus particles. 
     
     
         19 . The method of  claim 15 , wherein the therapeutically effective amount of said viral vector is about 1_× — 10 13  to about 5× — 10 13  virus particles. 
     
     
         20 . The method of  claim 3 , wherein said administering comprises intravenous administration. 
     
     
         21 . The method of  claim 3 , wherein said administering comprises local administration. 
     
     
         22 . The method of  claim 3 , wherein said administering is in at least two doses of said viral vector. 
     
     
         23 . The method of  claim 3 , wherein said administering is in at least three doses of said viral vector. 
     
     
         24 . The method of  claim 3 , wherein the viral vector is administered as a single unit dose. 
     
     
         25 . The method of  claim 3 , wherein the Fas-c comprises an extracellular domain of TNFR1 and a trans-membrane region and an intracellular region of Fas polypeptide. 
     
     
         26 . The method of  claim 25 , wherein the Fas-c comprises SEQ ID NO: 2 and SEQ ID NO: 3. 
     
     
         27 . The method of  claim 3 , further comprising administering to the subject an anti-cancer drug. 
     
     
         28 . The method of  claim 27 , wherein said anti-cancer drug is bevacizumab. 
     
     
         29 . The method of  claim 3 , further comprising administering a therapy selected from the group consisting of chemotherapy, radiotherapy, phototherapy and photodynamic therapy, surgery, nutritional therapy, ablative therapy, brachiotherapy, proton beam therapy, immunotherapy, cellular therapy and photon beam radiosurgical therapy. 
     
     
         30 . The method of  claim 28 , wherein said therapy is immunotherapy.