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.

What is claimed is: 
     
         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  or  claim 2 , 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 . A method for obtaining a complete response in a subject with refractory metastatic cancer, comprising administering an effective amount of a combination of 1,3-bis(2-chloroethyl)-1-nitrosourea, doxorubicin and melphalan. 
     
     
         6 . A method for the treatment of metastatic cancer comprising, administering to a subject, a combination of compositions that induce oxidative stress in cancer cells; administering a DNA crosslinking agent; and administering an infusion of stored hematopoietic stem cells to the subject. 
     
     
         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 8  or  claim 7 , wherein the set of drugs also includes one or more drugs that hypersensitizes cancer cells to the crosslinking agent. 
     
     
         10 . The method any one of  claims 7 - 9 , wherein the set of drugs includes a drug that decreases detoxification of said crosslinking agent in cancer cells. 
     
     
         11 . The method of any one of  claims 7 - 10 , wherein the set of drugs includes a drug that decreases nucleotide excision repair of DNA. 
     
     
         12 . The method of any one of  claims 7 - 11 , wherein the set of drugs also includes a drug that inhibits repair of DNA interstrand crosslinks. 
     
     
         13 . The method of any one of  claims 7 - 13 , wherein said drug inhibits homologous recombination. 
     
     
         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 any one of  claims 9 - 18 , further including a redox cycling agent. 
     
     
         20 . The method of  claim 19  wherein said redox cycling agent is an anthracycline. 
     
     
         21 . The method of  claim 20  wherein said anthracycline is selected from doxorubicin, idarubicin, epirubicin, and daunorubicin or combinations thereof. 
     
     
         22 . The method of any one of  claims 9 - 21 ; wherein the crosslinking agent is melphalan. 
     
     
         23 . The method of  claim 12  or  13 , wherein said drug is a proteasome inhibitor. 
     
     
         24 . The method of  claim 23  wherein said proteasome inhibitor is carfilzomib or bortezomib. 
     
     
         25 . The method of  claim 9 , wherein the hypersensitization is caused by one or more compounds that inhibit detoxification of the crosslinking agent, and or inhibit of nucleotide excision repair, and/or inhibit DNA double strand break repair, and/or inhibit DNA interstrand crosslink repair and or inhibit of homologous recombination. 
     
     
         26 . The method of  claim 25 , wherein the crosslinking agent is melphalan. 
     
     
         27 . A method for effective treatment of refractory metastatic cancer; comprising the steps of;
 a) administering a dose of 1,3-bis(2-chloroethyl)-1-nitrosourea, and a dose of doxorubicin;   b) administering within 6 hours of step a), a dose of melphalan; and   c) optionally administering a proteasome inhibitor, wherein the melphalan is administered at a dose wherein the potential for cancer cell proliferation is irreversibly inhibited and the melphalan dose is in the range of 20 to 200 mg/m 2 .   
     
     
         28 . A method for treatment of metastatic cancer in a patient with metastatic cancer or refractory metastatic cancer; comprising;
 a) administering 70-300 mg/m 2  of 1,3-bis(2-chloroethyl)-1-nitrosourea;   b) administering 20-80 mg/m 2  of adriamycin;   c) administering 30 to 200 mg/m 2  Melphalan and   d) optionally administering one or more doses of kyprolis 20 mg/m 2  and repeating steps a-d if needed), wherein the potential for cancer cell proliferation is irreversibly inhibited.   
     
     
         29 . The method of  claim 6 , wherein the oxidative stress is obtained by the administration at least one agent selected from BCNU, (bis-chloroethylnitrosourea), 1-cyrlohexyl-3-(z-chloroethyl)-3-nitrosourea (CCNU) and 1,(4-trans-methylcyclohexyl)-3-(2-chlororethyl)-3-nitrosourea (MeCCNU) and at least one agent selected from doxorubicin, idarubicin, epirubicin, daunorubicin and methylene blue. 
     
     
         30 . The method of  claim 28 , wherein steps a and b are omitted in a subject with a BRCA-1 or a BRCA2-associated cancer. 
     
     
         31 . The method of  claim 16 , wherein the glutathione reductase inhibitor is carmustine (BCNU) at an intravenous dose of approximately 50-100 mg/m2. 
     
     
         32 . The method of  claim 29 , wherein the methylene blue at an intravenous dose of approximately 1-5 mg/kg. 
     
     
         33 . The method of any one of the preceding claims, 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 any one of the preceding claims, 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 any one of the preceding claim, further comprising stem cell transplantation therapy. 
     
     
         36 . A set of pharmaceutical composition for use in effectively treating metastatic cancer comprising a combination of 1,3-bis(2-chloroethyl)-1-nitrosourea, doxorubicin and melphalan and pharmaceutically acceptable salts thereof. 
     
     
         37 . Use of a pharmaceutical composition for treating metastatic cancer or refractory metastatic cancer in a subject, comprising a therapeutically effective dose of a combination of 1,3-bis(2-chloroethyl)-1-nitrosourea, doxorubicin and melphalan and optionally a proteasome inhibitor, wherein the melphalan dose is in the range of 20 to 200 mg/m 2 . 
     
     
         38 . A method for the treatment of metastatic cancer comprised of the following sequential steps:
 i. administering an inhibitor of the MDR1 pgp efflux pump   ii administering a set of drugs that induce oxidative stress in cancer cells   iii. administering a DNA crosslinking agent   iv. administering a proteasome inhibitor; and   v. administering an infusion of stored hematopoietic stem cells.   
     
     
         39 . A method of  claim 38 , wherein the pgp inhibitor is fluoxetine, the drugs that induce oxidative stress are carmustine and doxorubicin, the DNA crosslinking agent is melphalan and the proteasome inhibitor is Kyprolis.