Treatment of cancer with naltrexone

Abstract

The present invention provides novel therapeutic applications of low dose naltrexone (LDN). Said applications have been determined in light of the discovery by the present inventors that naltrexone acts as an antagonist of Toll-like receptor 9 (TLR9), an innate immune receptor which elicits the production of inflammatory cytokines when agonised. Chronic inflammation and TLR9 overexpression are characteristics of a number of disorders, including certain cancers. Accordingly, the present invention provides novel uses of naltrexone in the treatment of a subject having a disorder characterised by TLR9 overexpression and/or overactivity of TLR9-mediated signalling. The present invention also provides novel uses of naltrexone in the supportive care of subject having a tumour/cancer, and methods of treating and providing supportive care to a subject, comprising the administration of naltrexone.

1 . A pharmaceutical composition comprising naltrexone or an analogue thereof, for use in the treatment of a subject having a disorder which is characterised by TLR9 overexpression and/or overactivity of TLR9-mediated signalling. 
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein the subject is characterised as having TLR9 overexpression and/or overactivity of TLR9-mediated signalling. 
     
     
         3 . A pharmaceutical composition according to  claim 1 , wherein the disorder is a tumour/cancer. 
     
     
         4 . A pharmaceutical composition according to  claim 3 , wherein the tumour/cancer is selected from the group consisting of breast cancer, cervical squamous cell carcinoma, gastric carcinoma, glioma, hepatocellular carcinoma, lung cancer, melanoma, prostate cancer, recurrent glioblastoma, recurrent non-Hodgkin lymphoma, colorectal cancer. 
     
     
         5 . A pharmaceutical composition according to  claim 1 , wherein the subject is or has been administered at least one chemotherapeutic agent selected from the group consisting of Revlimid, cyclophosphamide, Gemcitabine and carboplatin. 
     
     
         6 . A pharmaceutical composition according to  claim 5 , wherein Revlimid is administered at a dose between 5 mg and 25 mg, cyclophosphamide is administered at a dose between 50 mg and 100 mg, and/or Gemcitabine is administered at a dose between 250 mg and 2000 mg. 
     
     
         7 . A pharmaceutical composition comprising naltrexone or an analogue thereof, for use in the supportive care of a subject having a tumour/cancer. 
     
     
         8 . A pharmaceutical composition according to  claim 7 , wherein the subject is characterised as having TLR9 overexpression and/or overactivity of TLR9-mediated signalling. 
     
     
         9 . A pharmaceutical composition according to  claim 8 , wherein macrophages; B cells; and/or dendritic cells, preferably plasmacytoid dendritic cells; of the subject are characterised as having TLR9 overexpression. 
     
     
         10 . A pharmaceutical composition according to  claim 7 , wherein said subject is or has been administered at least one other immunomodulator, preferably an immune agonist. 
     
     
         11 . A pharmaceutical composition according to  claim 10 , wherein the immune agonist is selected from the group consisting of cyclophosphamide, Revlimid, Imiquimod, a whole cell  Mycobacteria , Daunorubicin, Oxaliplatin, 5-Fluorouracil, Gemcitabine, Zometa. 
     
     
         12 . A pharmaceutical composition according to  claim 11 , wherein the whole cell  Mycobacteria  is a rough strain of  Mycobacteria obuense  or  Mycobacteria vaccae.    
     
     
         13 . A pharmaceutical composition according to  claim 1 , wherein naltrexone, as part of said composition, is to be administered to the subject at a dose between 0.01 mg/kg and 0.08 mg/kg, preferably between 0.03 mg/kg and 0.06 mg/kg, more preferably between 0.04 mg/kg and 0.05 mg/kg. 
     
     
         14 . A method of treating a subject having a disorder which is characterised by TLR9 overexpression and/or overactivity of TLR9-mediated signalling; wherein the method comprises administering to the subject, a pharmaceutical composition comprising naltrexone or an analogue thereof. 
     
     
         15 . A method according to  claim 14 , wherein the subject is characterised as having TLR9 overexpression and/or overactivity of TLR9-mediated signalling. 
     
     
         16 . A method according to  claim 15 , wherein the method additionally comprises testing the subject for TLR9 overexpression and/or overactivity of TLR9-mediated signalling. 
     
     
         17 . A method according to  claim 14 , wherein the disorder is a tumour/cancer. 
     
     
         18 . A method according to  claim 17 , wherein the tumour/cancer is selected from the group consisting of breast cancer, cervical squamous cell carcinoma, gastric carcinoma, glioma, hepatocellular carcinoma, lung cancer, melanoma, prostate cancer, recurrent glioblastoma, recurrent non-Hodgkin lymophoma, colorectal cancer. 
     
     
         19 . A method according to  claim 14 , wherein the subject is or has been administered at least one chemotherapeutic agent selected from the group consisting of Revilimid, cyclophosphamide, Gemcitabine and carboplatin. 
     
     
         20 . A method according to  claim 19 , wherein Revlimid is administered at a dose between 5 mg and 25 mg, cyclophosphamide is administered at a dose between 50 mg and 100 mg, and/or Gemcitabine is administered at a dose between 250 mg and 2000 mg. 
     
     
         21 . A method of providing supportive care to a subject having a tumour/cancer, comprising administering to the subject, a pharmaceutical composition comprising naltrexone or an analogue thereof. 
     
     
         22 . A method according to  claim 21 , wherein the subject is characterised as having TLR9 overexpression and/or overactivity of TLR9-mediated signalling. 
     
     
         23 . A method according to  claim 22 , wherein macrophages; B cells; and/or dendritic cells, preferably plasmacytoid dendritic cells; of the subject are characterised as having TLR9 overexpression. 
     
     
         24 . A method according to  claim 21 , wherein said subject is or has been administered at least one other immunomodulator, preferably an immune agonist. 
     
     
         25 . A method according to  claim 24 , wherein the immune agonist is selected from the group consisting of cyclophosphamide, Revlimid, Imiquimod, a whole cell  Mycobacteria , Daunorubicin, Oxaliplatin, 5-Fluorouracil, Gemcitabine, Zometa. 
     
     
         26 . A method according to  claim 25 , wherein the whole cell  Mycobacteria  is a rough strain of  Mycobacteria obuense  or  Mycobacteria vaccae.    
     
     
         27 . A method according to  claim 14 , wherein naltrexone, as part of said composition, is to be administered to the subject at a dose between 0.01 mg/kg and 0.08 mg/kg, preferably between 0.03 mg/kg and 0.06 mg/kg, more preferably between 0.04 mg/kg and 0.05 mg/kg. 
     
     
         28 - 35 . (canceled)