Use of substituted hexitols including dianhydrogalactitol and analogs to treat neoplastic disease and cancer stem cells including glioblastoma multforme and medulloblastoma

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of glioblastoma multiforme and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N 7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism.

What is claimed is: 
     
         1 . A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy employing a substituted hexitol derivative for the treatment of GBM comprising an alternative selected from the group consisting of:
 (a) a therapeutically effective quantity of a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative, wherein the modified substituted hexitol derivative or the derivative, analog or prodrug of the substituted hexitol derivative or modified substituted hexitol derivative possesses increased therapeutic efficacy or reduced side effects for treatment of GBM as compared with an unmodified substituted hexitol derivative;   (b) a composition comprising:
 (i) a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative; and 
 (ii) at least one additional therapeutic agent, therapeutic agent subject to chemosensitization, therapeutic agent subject to chemopotentiation, diluent, excipient, solvent system, drug delivery system, agent to counteract myelosuppression, or agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier, wherein the composition possesses increased therapeutic efficacy or reduced side effects for treatment of GBM as compared with an unmodified substituted hexitol derivative; 
   (c) a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage form, wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage form possesses increased therapeutic efficacy or reduced side effects for treatment of GBM as compared with an unmodified substituted hexitol derivative;   (d) a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is incorporated into a dosage kit and packaging, wherein the substituted hexitol derivative, the modified substituted hexitol derivative or the derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage kit and packaging possesses increased therapeutic efficacy or reduced side effects for treatment of GBM as compared with an unmodified substituted hexitol derivative; and   (e) a therapeutically effective quantity of a substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is subjected to a bulk drug product improvement, wherein substituted hexitol derivative, a modified substituted hexitol derivative or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative subjected to the bulk drug product improvement possesses increased therapeutic efficacy or reduced side effects for treatment of GBM as compared with an unmodified substituted hexitol derivative.   
     
     
         2 . The composition of  claim 1  wherein the unmodified substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol. 
     
     
         3 . The composition of  claim 2  wherein the unmodified substituted hexitol derivative is dianhydrogalactitol. 
     
     
         4 . The composition of  claim 1  wherein the composition comprises a drug combination comprising:
 (a) a substituted hexitol derivative; and 
 (b) an additional therapeutic agent selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) monofunctional alkylating agents; 
 (viii) bifunctional alkylating agents; 
 (ix) alkylating agents that damage DNA at a different place than does dianhydrogalactitol; 
 (x) anti-tubulin agents; 
 (xi) antimetabolites; 
 (xii) berberine; 
 (xiii) apigenin; 
 (xiv) amonafide; 
 (xv) colchicine or analogs; 
 (xvi) genistein; 
 (xvii) etoposide; 
 (xviii) cytarabine; 
 (xix) camptothecins; 
 (xx) vinca alkaloids; 
 (xxi) 5-fluorouracil; 
 (xxii) curcumin; 
 (xxiii) NF-κB inhibitors; 
 (xxiv) rosmarinic acid; 
 (xxv) mitoguazone; 
 (xxvi) tetrandrine; 
 (xxvii) temozolomide; 
 (xxviii) VEGF inhibitors; 
 (xxix) cancer vaccines; 
 (xxx) EGFR inhibitors; 
 (xxxi) tyrosine kinase inhibitors; and 
 (xxxii) poly (ADP-ribose) polymerase (PARP) inhibitors. 
 
 
     
     
         5 . The composition of  claim 4  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         6 . The composition of  claim 1  wherein the composition comprises:
 (a) a substituted hexitol derivative; and 
 (b) a therapeutic agent subject to chemosensitization or chemopotentiation selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) alkylating agents; 
 (viii) anti-tubulin agents; 
 (ix) antimetabolites; 
 (x) berberine; 
 (xi) apigenin; 
 (xii) amonafide; 
 (xiii) colchicine or analogs; 
 (xiv) genistein; 
 (xv) etoposide; 
 (xvi) cytarabine; 
 (xvii) camptothecins; 
 (xviii) vinca alkaloids; 
 (xix) topoisomerase inhibitors; 
 (xx) 5-fluorouracil; 
 (xxi) curcumin; 
 (xxii) NF-κB inhibitors; 
 (xxiii) rosmarinic acid; 
 (xxiv) mitoguazone; 
 (xxv) tetrandrine; 
 (xxvi) a tyrosine kinase inhibitor; 
 (xxvii) an inhibitor of EGFR; and 
 (xxviii) an inhibitor of PARP; 
 
 
       wherein the substituted hexitol derivative acts as a chemosensitizer or a chemopotentiator. 
     
     
         7 . The composition of  claim 6  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         8 . The composition of  claim 1  wherein the composition comprises:
 (a) a substituted hexitol derivative; and 
 (b) an agent to counteract myelosuppression. 
 
     
     
         9 . The composition of  claim 8  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         10 . The composition of  claim 1  wherein the composition comprises:
 (a) a substituted hexitol derivative; and 
 (b) an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier. 
 
     
     
         11 . The composition of  claim 10  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         12 . The composition of  claim 1  wherein the composition comprises a substituted hexitol derivative and a drug delivery system selected from the group consisting of:
 (i) nanocrystals; 
 (ii) bioerodible polymers; 
 (iii) liposomes; 
 (iv) slow release injectable gels; and 
 (v) microspheres. 
 
     
     
         13 . The composition of  claim 12  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         14 . The composition of  claim 1  wherein the substituted hexitol derivative is present in the composition in a drug conjugate form selected from the group consisting of:
 (i) a polymer system; 
 (ii) polylactides; 
 (iii) polyglycolides; 
 (iv) amino acids; 
 (v) peptides; and 
 (vi) multivalent linkers. 
 
     
     
         15 . The composition of  claim 14  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         16 . The composition of  claim 1  wherein the composition comprises a substituted hexitol derivative and at least one additional therapeutic agent to form a multiple drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of:
 (i) an inhibitor of multi-drug resistance; 
 (ii) a specific drug resistance inhibitor; 
 (iii) a specific inhibitor of a selective enzyme; 
 (iv) a signal transduction inhibitor; 
 (v) an inhibitor of a repair enzyme; and 
 (vi) a topoisomerase inhibitor with non-overlapping side effects. 
 
     
     
         17 . The composition of  claim 16  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         18 . A method of treating glioblastoma multiforme comprising the step of administering a therapeutically effective quantity of a substituted hexitol derivative to a patient suffering from the malignancy. 
     
     
         19 . The method of  claim 18  wherein the substituted hexitol derivative is selected from the group consisting of galactitols, substituted galacitols, dulcitols, and substituted dulcitols. 
     
     
         20 . The method of  claim 19  wherein the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, derivatives of dianhydrogalactitol, diacetyldianhydrogalactitol, derivatives of diacetyldianhydrogalactitol, dibromodulcitol, and derivatives of dibromodulcitol. 
     
     
         21 . The method of  claim 20  wherein the substituted hexitol derivative is dianhydrogalactitol. 
     
     
         22 . The method of  claim 21  wherein the therapeutically effective quantity of dianhydrogalactitol is a quantity of dianhydrogalactitol that results in a dosage of from about 1 mg/m 2  to about 40 mg/m 2 . 
     
     
         23 . The method of  claim 22  wherein the therapeutically effective quantity of dianhydrogalactitol is a quantity of dianhydrogalactitol that results in a dosage of from about 5 mg/m 2  to about 25 mg/m 2 . 
     
     
         24 . The method of  claim 21  wherein the dianhydrogalactitol is administered by a route selected from the group consisting of intravenous and oral. 
     
     
         25 . The method of  claim 18  further comprising a step selected from the group consisting of:
 (a) administering a therapeutically effective dose of ionizing radiation; 
 (b) administering a therapeutically effective quantity of temozolomide; 
 (c) administering a therapeutically effective quantity of bevacizumab; 
 (d) administering a therapeutically effective quantity of a corticosteroid; 
 (e) administering a therapeutically effective quantity of at least one chemotherapeutic agent selected from the group consisting of lomustine, cisplatin, carboplatin, vincristine, and cyclophosphamide; 
 (f) administering a therapeutically effective quantity of a tyrosine kinase inhibitor; and 
 (g) administering a therapeutically effective quantity of an EGFR inhibitor. 
 
     
     
         26 . The method of  claim 21  wherein the dianhydrogalactitol substantially suppresses the growth of cancer stem cells (CSCs). 
     
     
         27 . The method of  claim 21  wherein the dianhydrogalactitol is effective in suppressing the growth of cancer cells possessing O 6 -methylguanine-DNA methyltransferase (MGMT)-driven drug resistance. 
     
     
         28 . The method of  claim 21  wherein the dianhydrogalactitol is effective in suppressing the growth of cancer cells resistant to temozolomide. 
     
     
         29 . The method of  claim 25  wherein the method comprises administering a therapeutically effective quantity of an EGFR inhibitor and wherein the EGFR inhibitor affects wild-type binding sites. 
     
     
         30 . The method of  claim 25  wherein the method comprises administering a therapeutically effective quantity of an EGFR inhibitor and wherein the EGFR inhibitor affects mutated binding sites. 
     
     
         31 . The method of  claim 30  wherein the EGFR inhibitor affects EGFR Variant III.