Methods of treatment of temozolomide-resistant glioma using coenzyme q10

Abstract

The invention provides methods and compositions for treatment of a subject with a glioma that has failed treatment with temozolomide (TMZ) comprising administration of a composition comprising a Coenzyme Q10 compound to the subject. The invention also provides a method of treating a cancer that exhibits increased Complex II activity in a subject comprising administration of a composition comprising a Coenzyme Q10 compound to the subject.

We claim: 
     
         1 . A method of treating a glioma in a subject, wherein the subject has failed treatment for the glioma with temozolomide (TMZ), the method comprising administering to the subject a composition comprising a Coenzyme Q10 compound, thereby treating the glioma in the subject. 
     
     
         2 . The method of  claim 1 , wherein the glioma is a glioblastoma. 
     
     
         3 . The method of  claim 1 , wherein the glioma is a refractory glioma. 
     
     
         4 . The method of  claim 3 , wherein the glioma is refractory to an anti-cancer agent selected from the group consisting of TMZ and bevacizumab. 
     
     
         5 . The method of  claim 1 , wherein the glioma exhibits increased Complex II activity relative to a glioma that is not TMZ-resistant. 
     
     
         6 . The method of  claim 1 , wherein the subject has failed treatment for the glioma with at least one additional anti-cancer agent. 
     
     
         7 . The method of  claim 6 , wherein the at least one additional anti-cancer agent is a chemotherapeutic agent. 
     
     
         8 . The method of  claim 6 , wherein the at least one additional anti-cancer agent is an anti-angiogenic agent. 
     
     
         9 . The method of  claim 6 , wherein the at least one additional anti-cancer agent is bevacizumab. 
     
     
         10 . The method of  claim 1 , wherein the failed treatment comprises tumor growth during or after treatment with the TMZ. 
     
     
         11 . The method of  claim 6 , wherein the failed treatment comprises tumor growth during or after treatment with the at least one additional anti-cancer agent. 
     
     
         12 . The method of  claim 1 , wherein the subject demonstrates a clinical benefit as a result of administration of the composition comprising the Coenzyme Q10 compound. 
     
     
         13 . The method of  claim 12 , wherein the clinical benefit is selected from the group consisting of stable disease per RECIST 1.1 criteria, partial response per RECIST 1.1 criteria, and complete response per RECIST 1.1 criteria. 
     
     
         14 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the glioma comprises a Stage III or Stage IV tumor. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the glioma is a low grade glioma. 
     
     
         22 . The method of  claim 1 , wherein the glioma is a high grade glioma. 
     
     
         23 . The method of  claim 1 , wherein the glioma is metastatic. 
     
     
         24 . The method of  claim 1 , wherein the subject has further failed treatment with a chemotherapeutic agent selected from the group consisting of carmustine (BCNU), thalidomide, irinotecan, lomustine (CCNU), procarbazine, vincristine, and a platinum compound. 
     
     
         25 . The method of  claim 1 , wherein the Coenzyme Q10 compound is Coenzyme Q10. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25 , wherein the Coenzyme Q10 is administered at a dose selected from the group consisting of at least 15.5 mg/kg/day (24 hours), at least 16.7 mg/kg/day (24 hours), at least 19.0 mg/kg/day (24 hours), at least 20.5 mg/kg/day (24 hours), at least 22.0 mg/kg/day (24 hours), at least 25.0 mg/kg/day (24 hours), at least 27.3 mg/kg/day (24 hours), at least 29.3 mg/kg/day (24 hours), at least 33.4 mg/kg/day (24 hours), at least 36.7 mg/kg/day (24 hours), at least 34.1 mg/kg/day (24 hours), at least 41.7 mg/kg/day (24 hours), at least 42.5 mg/kg/day (24 hours), at least 45.7 mg/kg/day (24 hours), at least 52.0 mg/kg/day (24 hours), at least 53.1 mg/kg/day (24 hours), at least 57 mg/kg/day (24 hours), at least 64.9 mg/kg/day (24 hours), at least 66.7 mg/kg/day (24 hours), at least 71.7 mg/kg/day (24 hours), at least 81.5 mg/kg/day (24 hours), at least 88.8 mg/kg/day (24 hours), at least 95.3 mg/kg/day (24 hours), at least 108.5 mg/kg/day (24 hours), at least 117.9 mg/kg/day (24 hours), at least 126.7 mg/kg/day (24 hours), at least 144.2 mg/kg/day (24 hours), at least 156.7 mg/kg/day (24 hours), at least 168.3 mg/kg/day (24 hours), at least 191.6 mg/kg/day (24 hours), at least 208.5 mg/kg/day (24 hours), at least 224 mg/kg/day (24 hours), and at least 254.9 mg/kg/day (24 hours). 
     
     
         28 . The method of  claim 25 , wherein the Coenzyme Q10 is administered at a dose selected from the group consisting of at least 100 mg/kg/week, at least 132 mg/kg/week, at least 171 mg/kg/week, at least 176 mg/kg/week, at least 215 mg/kg/week, at least 220 mg/kg/week, at least 274 mg/kg/week, at least 342 mg/kg/week, at least 430 mg/kg/week, at least 572 mg/kg/week, at least 760 mg/kg/week, at least 1010 mg/kg/week, and at least 1344 mg/kg/week. 
     
     
         29 . The method of  claim 25 , wherein the Coenzyme Q10 is administered at a dose selected from the group consisting of about 100 mg/kg/week, about 132 mg/kg/week, about 171 mg/kg/week, about 176 mg/kg/week, about 215 mg/kg/week, about 220 mg/kg/week, about 274 mg/kg/week, about 342 mg/kg/week, about 430 mg/kg/week, about 572 mg/kg/week, about 760 mg/kg/week, about 1010 mg/kg/week, and about 1344 mg/kg/week. 
     
     
         30 . The method of  claim 25 , wherein the Coenzyme Q10 is administered at a dose selected from the group consisting of at least 50 mg/kg/dose, at least 66 mg/kg/dose, at least 88 mg/kg/dose, at least 110 mg/kg/dose, at least 137 mg/kg/dose, at least 171 mg/kg/dose, at least 215 mg/kg/dose, at least 286 mg/kg/dose, at least 380 mg/kg/dose, at least 505 mg/kg/dose, and at least 672 mg/kg/dose. 
     
     
         31 . The method of  claim 25 , wherein the Coenzyme Q10 is administered at a dose selected from the group consisting of about 50 mg/kg/dose, about 66 mg/kg/dose, about 88 mg/kg/dose, about 110 mg/kg/dose, about 137 mg/kg/dose, about 171 mg/kg/dose, about 215 mg/kg/dose, about 286 mg/kg/dose, about 380 mg/kg/dose, about 505 mg/kg/dose, and about 672 mg/kg/dose. 
     
     
         32 . The method of  claim 1 , wherein the composition comprising the Coenzyme Q10 compound is administered by injection or infusion. 
     
     
         33 . The method of  claim 1 , wherein the composition comprising the Coenzyme Q10 compound is administered intravenously. 
     
     
         34 . The method of  claim 1 , wherein the composition comprising the Coenzyme Q10 is administered by continuous infusion. 
     
     
         35 . The method of  claim 34 , wherein the composition comprising the Coenzyme Q10 is administered by continuous infusion for at least 48 hours or at least 72 hours, at least 96 hours, at least 120 hours, or at least 144 hours. 
     
     
         36 . The method of  claim 30 , wherein the dose of Coenzyme Q10 is administered by continuous infusion over about 72 hours. 
     
     
         37 - 42 . (canceled) 
     
     
         43 . The method of  claim 1 , wherein the subject is human 
     
     
         44 . The method of  claim 1 , wherein the composition comprising the Coenzyme Q10 compound is administered to the subject with an additional anti-cancer agent. 
     
     
         45 . The method of  claim 44 , wherein the additional anti-cancer agent is a chemotherapeutic agent. 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 44 , wherein the additional anti-cancer agent is bevacizumab, TMZ or a combination thereof. 
     
     
         48 . A method of treating a cancer that exhibits increased Complex II activity in a subject, the method comprising administering to the subject a composition comprising a Coenzyme Q10 compound, thereby treating the cancer that exhibits increased Complex II activity in the subject. 
     
     
         49 . The method of  claim 48 , wherein the subject has failed treatment for the cancer with at least one anti-cancer agent. 
     
     
         50 - 51 . (canceled) 
     
     
         52 . The method of  claim 48 , wherein the subject demonstrates a clinical benefit as a result of administration of the composition comprising the Coenzyme Q10 compound. 
     
     
         53 . The method of  claim 52 , wherein the clinical benefit is selected from the group consisting of stable disease per RECIST 1.1 criteria, partial response per RECIST 1.1 criteria, and complete response per RECIST 1.1 criteria. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 48 , wherein the Coenzyme Q10 compound is Coenzyme Q10. 
     
     
         56 - 68 . (canceled)