Use of dianhydrogalactitol or derivatives or analogs thereof for treatment of pediatric central nervous system malignancies

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of malignancies of the central nervous system in pediatric patients, including glioblastoma multiforme (GBM) high grade glioma, and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N 7 methylation and that can induce double-stranded breaks in DNA. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents (e.g. cisplatin) and can possess additive or super-additive effects.

What is claimed is: 
     
         1 . A method for treating glioblastoma multiforme or medulloblastoma comprising the step of administering a therapeutically effective quantity of dianhydrogalactitol or a derivative or analog thereof to a patient with glioblastoma multiforme or medulloblastoma resistant to a nitrosourea to treat the glioblastoma multiforme or medulloblastoma. 
     
     
         2 . The method of  claim 1  wherein the dianhydrogalactitol or a derivative or analog thereof is dianhydrogalactitol. 
     
     
         3 . The method of  claim 1  wherein the patient with glioblastoma multiforme or medulloblastoma resistant to a nitrosourea is a pediatric patient. 
     
     
         4 . The method of  claim 1  wherein the patient with glioblastoma multiforme or medulloblastoma resistant to a nitrosourea is an adult patient. 
     
     
         5 . The method of  claim 1  wherein the nitrosourea is lomustine. 
     
     
         6 . The method of  claim 1  wherein the nitrosourea is selected from the group consisting of arabinopyranosyl-N-methyl-N-nitrosourea, carmustine, chlorozotocin, fotemustine, nimustine, ranimustine, semustine, and streptozotocin. 
     
     
         7 . A method for treating glioblastoma multiforme or medulloblastoma comprising the steps of:
 (a) administering a therapeutically effective quantity of dianhydrogalactitol or a derivative or analog thereof; and   (b) administering a therapeutically effective quantity of a topoisomerase inhibitor;   
       to a patient with glioblastoma multiforme or medulloblastoma to treat the glioblastoma multiforme or medulloblastoma. 
     
     
         8 . The method of  claim 7  wherein the dianhydrogalactitol or a derivative or analog thereof is dianhydrogalactitol. 
     
     
         9 . The method of  claim 7  wherein the patient with glioblastoma multiforme or medulloblastoma is a pediatric patient. 
     
     
         10 . The method of  claim 7  wherein the patient with glioblastoma multiforme or medulloblastoma is an adult patient. 
     
     
         11 . The method of  claim 7  wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 
     
     
         12 . The method of  claim 11  wherein the topoisomerase I inhibitor is camptothecin. 
     
     
         13 . The method of  claim 7  wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 
     
     
         14 . The method of  claim 13  wherein the topoisomerase II inhibitor is etoposide. 
     
     
         15 . The method of  claim 7  wherein the dianhydrogalactitol or a derivative or analog thereof and the topoisomerase inhibitor exhibit synergy. 
     
     
         16 . A method for treating glioblastoma multiforme or medulloblastoma comprising the steps of:
 (a) administering a therapeutically effective quantity of dianhydrogalactitol or a derivative or analog thereof; and   (b) administering a therapeutically effective quantity of an agent that requires malignant cells to be in the S/G2 phase of the cell cycle for maximum therapeutic effect;   
       to a patient with glioblastoma multiforme or medulloblastoma to treat the glioblastoma multiforme or medulloblastoma. 
     
     
         17 . The method of  claim 16  wherein the dianhydrogalactitol or a derivative or analog thereof is dianhydrogalactitol. 
     
     
         18 . The method of  claim 16  wherein the patient with glioblastoma multiforme or medulloblastoma is a pediatric patient. 
     
     
         19 . The method of  claim 16  wherein the patient with glioblastoma multiforme or medulloblastoma is an adult patient. 
     
     
         20 . The method of  claim 16  wherein the dianhydrogalactitol or a derivative or analog thereof and the agent that requires malignant cells to be in the S/G2 phase of the cell cycle for maximum therapeutic effect exhibit synergy. 
     
     
         21 . A method for treating glioblastoma multiforme or medulloblastoma comprising the step of administering a therapeutically effective quantity of dianhydrogalactitol or a derivative or analog thereof to a patient with glioblastoma multiforme or medulloblastoma to overcome mismatch repair (MMR)-mediated chemoresistance to treat the glioblastoma multiforme or medulloblastoma. 
     
     
         22 . The method of  claim 21  wherein the dianhydrogalactitol or a derivative or analog thereof is dianhydrogalactitol. 
     
     
         23 . The method of  claim 21  wherein the patient with glioblastoma multiforme or medulloblastoma is a pediatric patient. 
     
     
         24 . The method of  claim 21  wherein the patient with glioblastoma multiforme or medulloblastoma is an adult patient. 
     
     
         25 . A method for treating glioblastoma multiforme or medulloblastoma comprising the step of administering a therapeutically effective quantity of dianhydrogalactitol or a derivative or analog thereof to a patient with glioblastoma multiforme or medulloblastoma to induce persistent cell cycle arrest through a p53-independent pathway to treat the glioblastoma multiforme or medulloblastoma. 
     
     
         26 . The method of  claim 25  wherein the dianhydrogalactitol or a derivative or analog thereof is dianhydrogalactitol. 
     
     
         27 . The method of  claim 25  wherein the patient with glioblastoma multiforme or medulloblastoma is a pediatric patient. 
     
     
         28 . The method of  claim 25  wherein the patient with glioblastoma multiforme or medulloblastoma is an adult patient.