Methods for the Effective Treatment of Metastatic Cancer

Abstract

The present invention relates to methods for the treatment of metastatic cancer. Methods of treating metastatic cancer by administration of a set of drugs overcome multiple mechanisms of melphalan resistance and hypersensitize cancer cells to melphalan are described. The methods involve the administration of drug(s) that induce oxidative stress in cancer cells, in conjunction with melphalan on a defined schedule.

1 . A method of treating metastatic cancer or refractory metastatic cancer in a subject, comprising administering a combination of 1,3-bis(2-chloroethyl)-1-nitrosourea, doxorubicin and melphalan or pharmaceutically acceptable salts thereof simultaneously or within a six hour time period, and optionally administering a proteasome inhibitor within the 6 hour period or within the following 24 hours; wherein the melphalan dose is in the range of 20 to 200 mg/m 2 . 
     
     
         2 . A method for an effective treatment of metastatic cancer or refractory metastatic cancer in a subject, comprising administering an effective dose of a combination of 1,3-bis(2-chloroethyl)-1-nitrosourea, doxorubicin and melphalan; and optionally administering a proteasome inhibitor. 
     
     
         3 . The method of  claim 1 , wherein 1,3-bis(2-chloroethyl)-1-nitrosourea is administered at a dose range of 50 to 300 mg/m 2 ; the doxorubicin is administered at a dose of 10 to 80 mg/m 2 ; the melphalan is administered at a dose of 20 to 200 mg/m 2 ; and wherein the proteasome inhibitor is carfilzomib administered at a dose of 0 or 10 to 60 mg/m 2  or alternatively bortezomib is administered at a dose of 0 or 1 to 1.3 mg/m 2 . 
     
     
         4 . The method of  claim 3 , wherein 1,3-bis(2-chloroethyl)-1-nitrosourea is administered at a dose range of 100 mg/m 2 ; the doxorubicin is administered at a dose of 40 mg/m 2 ; and the carfilzomib is administered at a dose of 20 mg/m 2 . 
     
     
         5 .- 6 . (canceled) 
     
     
         7 . A method for the effective treatment of metastatic cancer in a subject comprised of the administration of a combination of one or more drugs, wherein said combination of drugs irreversibly inhibits the potential for cancer cell proliferation and wherein said method has improved patient outcome compared to current established therapies for the particular type of metastatic cancer. 
     
     
         8 . The method of  claim 7 , wherein the set of drugs comprises a DNA crosslinking agent. 
     
     
         9 . The method of  claim 7 , wherein the set of drugs also includes one or more drugs that hypersensitizes cancer cells to the crosslinking agent. 
     
     
         10 . The method  claim 7 , wherein the set of drugs includes a drug that decreases detoxification of said crosslinking agent in cancer cells. 
     
     
         11 . The method of  claim 7 , wherein the set of drugs includes a drug that decreases nucleotide excision repair of DNA. 
     
     
         12 . The method of  claim 7 , wherein the set of drugs also includes a drug that inhibits repair of DNA interstrand crosslinks. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 9  wherein said drug(s) induces oxidative stress or decrease intracellular GSH levels or increase the intracellular (GSSG)/(GSH)2 reduction potential, or increase levels of reactive oxygen species or inhibit the function of redox-sensitive proteins or increase glutathionylation of proteins in cancer cells. 
     
     
         15 . The method of  claim 14 , wherein the set of drugs includes an electrophilic thiol-reactive drug or a drug that gives rise to an electrophilic thiol reactive species. 
     
     
         16 . The method of  claim 14 , wherein the set of drugs includes an inhibitor to glutathione reductase or an inhibitor to thioredoxin reductase or one or more inhibitor(s) to both glutathione reductase and thioredoxin reductase. 
     
     
         17 . The method of  claim 16 , wherein said inhibitor is 1,3-bis(2-chloroethyl)-1-nitrosourea. 
     
     
         18 . The method of  claim 16 , wherein said inhibitor is (bis-chloroethylnitrosourea), 1-cyrlohexyl-3-(z-chloroethyl)-3-nitrosourea (CCNU). 
     
     
         19 . The method of  claim 9 , further including a redox cycling agent. 
     
     
         20 .- 21 . (canceled) 
     
     
         22 . The method of  claim 9 ; wherein the crosslinking agent is melphalan. 
     
     
         23 .- 32 . (canceled) 
     
     
         33 . The method of  claim 7 , wherein the cancer is refractory to prior melphalan therapy or a type of cancer that is known to be refractory to melphalan. 
     
     
         34 . The method of  claim 7 , wherein the cancer is selected from malignant melanoma, pancreatic cancer, ovarian cancer, breast cancer (stage iv), cervical cancer ureter cancer, prostate cancer. 
     
     
         35 . The method of  claim 7 , further comprising stem cell transplantation therapy. 
     
     
         36 .- 39 . (canceled)