Cancer therapy

Abstract

The present application relates to compositions and methods for treating a proliferative disorder by administering to a subject a pharmaceutical composition of a dual kinase inhibitor. Catecholic butanes cane serve as dual kinase inhibitors for purposes of methods described herein. Subjects can be further treated by co-administering an EGFR inhibitor. The present application also relates to analyzing a sample with respect to levels of IGF-1R and EGFR and comparing levels of IGF-1R and EGFR to a control. Patients can be selected for treatment with a catecholic butane based on the assessment; optionally, patients can be further treated with an EGFR inhibitor, an IGF-1R inhibitor, or both.

What is claimed is: 
     
         1 . A method for treating a disease in a subject, wherein the subject has developed resistance to treatment with one or more tyrosine-kinase inhibitors, comprising administering an effective amount of a pharmaceutical compound capable of inhibiting the tyrosine kinase activity of both IGF-1R and EGFR. 
     
     
         2 . The method of  claim 1 , wherein the subject has developed resistance to one or more of an EGF-R inhibitor or an IGF-1R inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the disease is malignant, pre-malignant or benign cancer. 
     
     
         4 . The method of  claim 3 , wherein the cancer is selected from the group consisting of brain tumor, carcinoma, basalioma, basal cell carcinoma, teratoma, retinoblastoma, neuroblastoma, melanoma, choroidea melanoma, Dermatofibrosarcoma protuberans, Merkel cell carcinoma or Kaposi's sarcoma, seminoma, sarcoma, plasmocytoma, head and neck tumor, liver tumor, kidney tumor, renal cell tumor, squamous cell carcinoma, uterine tumor, endometrial tumor, bone tumor, prostate tumor, breast tumor, bladder tumor, pancreatic tumor, endometrium tumor, squamous cell carcinoma, stomach tumor, gliomas, glioblastoma multiforme, colorectal tumor, testicular tumor, colon tumor, rectal tumor, ovarian tumor, cervical tumor, eye tumor, central nervous system tumor, thyroid tumor, lung tumor, leukemia or lymphoma, multiple myeloma, skin tumor, a gynecologic tumor, Hodgkin's disease, cancer of the small intestine, cancer of the endocrine system, mesothelioma, cancer of the urethra, cancer of the penis, tumors related to Gorlin's syndrome, and tumor of unknown origin; and metastases thereto. 
     
     
         5 . The method of  claim 1 , wherein the pharmaceutical compound comprises a catecholic butane of formula I, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, metabolites thereof, tautomers thereof or prodrugs thereof: 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently H, lower alkyl, or lower acyl; 
         R3, R4, R5, R6, R10, R11, R12 and R13 are independently H or lower alkyl; and 
         R7, R8 and R9 are independently H, hydroxy, lower alkoxy or lower acyloxy. 
       
     
     
         6 . The method of  claim 5 , wherein the catecholic butane is selected from the group consisting of 1,4-bis(3,4-dihydroxphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dihydroxyphenyl)butane; 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-diethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropoxyphenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4-(3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diacetoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropionyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dibutyroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-divaleroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipivaloyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dineopentylcarboxylphenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4-phenylbutane; 1-(3,4-dihydroxyphenyl)-4-(2,5-dihydroxyphenyl)butane, nordihydroruaiaretic acid (NDGA), tetra-O-methyl NDGA; tetraglycinyl NDGA; tetra-dimethylglycinyl NDGA or a salt thereof; or tri-O-methyl NDGA; nordihydroguaiaretic acid tetrapivalate; nordihydroguaiaretic acid tetrapropionate and all optical configurations thereof. 
     
     
         7 . The method of  claim 5 , wherein the catecholic butane is nordihydroguaiaretic acid. 
     
     
         8 . A method for treating cancer in a subject, wherein said subject has developed resistance to treatment with one or more tyrosine-kinase inhibitors, comprising administering an effective amount of a pharmaceutical composition capable of inhibiting the tyrosine kinase activity of both IGF-1R and EGFR, wherein the pharmaceutical composition comprises a catecholic butane. 
     
     
         9 . The method of  claim 8 , wherein the subject has developed resistance to one or more EGF-R inhibitors or IGF-1R inhibitors. 
     
     
         10 . The method of  claim 8 , wherein the cancer is selected from the group consisting of a solid tumor, lymphoma, leukemia, epithelial-based cancer, brain tumor, carcinoma, basalioma, basal cell carcinoma, teratoma, retinoblastoma, neuroblastoma, melanoma, choroidea melanoma, Dermatofibrosarcoma protuberans, Merkel cell carcinoma or Kaposi's sarcoma, seminoma, sarcoma, plasmocytoma, head and neck tumor, liver tumor, kidney tumor, renal cell tumor, squamous cell carcinoma, uterine tumor, endometrial tumor, bone tumor, prostate tumor, breast tumor, bladder tumor, pancreatic tumor, endometrium tumor, squamous cell carcinoma, stomach tumor, gliomas, glioblastoma multiforme, colorectal tumor, testicular tumor, colon tumor, rectal tumor, ovarian tumor, cervical tumor, eye tumor, central nervous system tumor, thyroid tumor, lung tumor, leukemia or lymphoma, multiple myeloma, skin tumor, a gynecologic tumor, Hodgkin's disease, cancer of the small intestine, cancer of the endocrine system, mesothelioma, cancer of the urethra, cancer of the penis, tumors related to Gorlin's syndrome, and tumor of unknown origin; and metastases thereto. 
     
     
         11 . The method of  claim 8 , wherein the pharmaceutical composition comprises a catecholic butane of formula I, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, metabolites thereof, tautomers thereof or prodrugs thereof: 
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently H, lower alkyl, or lower acyl; 
         R3, R4, R5, R6, R10, R11, R12 and R13 are independently H or lower alkyl; and 
         R7, R8 and R9 are independently H, hydroxy, lower alkoxy or lower acyloxy. 
       
     
     
         12 . The method of  claim 8 , wherein the pharmaceutical composition comprises a catecholic butane of formula II, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, metabolites thereof, tautomers thereof or prodrugs thereof: 
       
         
           
           
               
               
           
         
         wherein R5, R10, R6, and R13 are independently H; 
         when R3 is H, R11 is lower alkyl; or when R3 is lower alkyl, R11 is H; 
         when R4 is H, R12 is lower alkyl; or when R4 is lower alkyl, R12 is H; 
         two of R7, R8, and R9 are hydroxy, the other is H, and one of the hydroxy groups is in the 3-position and the other hydroxy group is in the 4-position relative to the alkylene substituent. 
       
     
     
         13 . The method of  claim 8 , wherein the catecholic butane is selected from the group consisting of 1,4-bis(3,4-dihydroxphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dihydroxyphenyl)butane; 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-diethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropoxyphenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4-(3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diacetoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropionyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dibutyroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-divaleroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipivaloyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dineopentylcarboxylphenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4-phenylbutane; 1-(3,4-dihydroxyphenyl)-4-(2,5-dihydroxyphenyl)butane, nordihydroruaiaretic acid (NDGA), tetra-O-methyl NDGA; tetraglycinyl NDGA; tetra-dimethylglycinyl NDGA or a salt thereof; or tri-O-methyl NDGA; nordihydroguaiaretic acid tetrapivalate; nordihydroguaiaretic acid tetrapropionate and all optical configurations thereof. 
     
     
         14 . The method of  claim 8 , wherein the catecholic butane is nordihydroguaiaretic acid. 
     
     
         15 . The method of  claim 8 , wherein the catecholic butane is administered in an amount selected from the group consisting of about 5 mg/kg to about 375 mg/kg per dose; about 5 mg/kg to about 250 mg/kg per dose; about 5 mg/kg to about 200 mg/kg per dose; about 5 mg/kg to about 150 mg/kg per dose; about 5 mg/kg to about 100 mg/kg per dose; about 5 mg/kg to about 75 mg/kg per dose; and about 5 mg/kg to about 50 mg/kg per dose. 
     
     
         16 . The method of  claim 8 , wherein the catecholic butane is administered in an amount selected from the group consisting of from about 1,500 mg per day to about 2,500 mg per day; from about 1,800 mg per day to about 2,300 mg per day; and about 2,000 mg per day. 
     
     
         17 . The method of  claim 8 , further comprising administering one or more additional anti cancer agents. 
     
     
         18 . The method of  claim 17 , wherein said one or more additional anti-cancer agents is selected from the group consisting of EGFR inhibitors, IGF-1R inhibitors, DNA damaging agents, Topoisomerase inhibitors and Mitotic inhibitors. 
     
     
         19 . The method of  claim 8 , wherein the pharmaceutical composition is administered more frequently than once every 6 days for a period of time, or more frequently than once every 2 days for a period of time. 
     
     
         20 . A method for determining a disease treatment, comprising:
 (i) analyzing a sample obtained from a subject comprising measuring levels of IGF-1R and EGFR, and   (ii) comparing the levels of the IGF-1R and EGFR in the sample to the levels in a control;   wherein increased levels of IGF-1R, EGFR, or both as compared to the control indicate that the subject is to be treated with a dual tyrosine kinase inhibitor.   
     
     
         21 . The method of  claim 20 , wherein the level of EGFR expression is at baseline levels or greater than baseline levels and where the level of IGF-1R expression is at baseline levels or greater than baseline levels. 
     
     
         22 . The method of  claim 21 , wherein the level of EGFR expression is at baseline levels and the level of IGF-1R expression is at 2× greater than baseline levels or more; the level of IGF-1R expression is at baseline levels and the level of EGFR expression is at 2× greater than baseline levels or more; or the level of IGF-1R expression is at 2× greater than baseline levels or more and the level of EGFR expression is at 2× greater than baseline levels or more. 
     
     
         23 . The method of  claim 20 , wherein the dual tyrosine kinase inhibitor is a catecholic butane. 
     
     
         24 . The method of  claim 23 , wherein the catecholic butane is selected from the group consisting of 1,4-bis(3,4-dihydroxphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dihydroxyphenyl)butane; 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-diethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropoxyphenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4-(3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diacetoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropionyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dibutyroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-divaleroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipivaloyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dineopentylcarboxylphenyl)-2,3-dimethylbutane; dihydroxyphenyl)-4-phenylbutane; 1-(3,4-dihydroxyphenyl)-4-(2,5-dihydroxyphenyl)butane, nordihydroguaiaretic acid (NDGA), tetra-O-methyl NDGA; tetraglycinyl NDGA; tetra-dimethylglycinyl NDGA or a salt thereof; or tri-O-methyl NDGA; nordihydroguaiaretic acid tetrapivalate; nordihydroguaiaretic acid tetrapropionate and all optical configurations thereof. 
     
     
         25 . The method of  claim 23 , wherein the catecholic butane is administered in an amount selected from the group consisting of about 5 mg/kg to about 375 mg/kg per dose; about 5 mg/kg to about 250 mg/kg per dose; about 5 mg/kg to about 200 mg/kg per dose; about 5 mg/kg to about 150 mg/kg per dose; about 5 mg/kg to about 100 mg/kg per dose; about 5 mg/kg to about 75 mg/kg per dose; and about 5 mg/kg to about 50 mg/kg per dose. 
     
     
         26 . The method of  claim 23 , wherein the catecholic butane is administered in an amount selected from the group consisting of from about 1,500 mg per day to about 2,500 mg per day; from about 1,800 mg per day to about 2,300 mg per day; and about 2,000 mg per day. 
     
     
         27 . The method of  claim 23 , wherein the catecholic butane is administered more frequently than once every 6 days for a period of time, or more frequently than once every 2 days for a period of time. 
     
     
         28 . The method of  claim 20 , further comprising administering one or more additional anti cancer agents. 
     
     
         29 . The method of  claim 28 , wherein said one or more additional anti-cancer agents is selected from the group consisting of EGFR inhibitors, IGF-1R inhibitors, DNA damaging agents, topoisomerase inhibitors and mitotic inhibitors. 
     
     
         30 . A method of selecting a subject for treatment with a dual tyrosine kinase inhibitor capable of inhibiting the tyrosine kinase activity of both IGF-1R and EGF-R, wherein said subject is identified as having levels of IGF-1R, EGFR, or both at baseline levels or at 2× greater than baseline levels as compared to control levels. 
     
     
         31 . The method of  claim 30 , wherein the level of EGFR expression is at baseline levels and the level of IGF-1R expression is at 2× greater than baseline levels or more; the level of IGF-1R expression is at baseline levels and the level of EGFR expression is at 2× greater than baseline levels or more; or the level of IGF-1R expression is at 2× greater than baseline levels or more and the level of EGFR expression is at 2× greater than baseline levels or more. 
     
     
         32 . The method of  claim 30 , wherein said subject is resistant to treatment with at least one tyrosine kinase inhibitor. 
     
     
         33 . The method of  claim 32 , wherein the subject has developed resistance to one or more EGF-R inhibitors or IGF-1R inhibitors. 
     
     
         34 . The method of  claim 30 , wherein the dual tyrosine kinase inhibitor is a catecholic butane. 
     
     
         35 . The method of  claim 34 , wherein the catecholic butane is selected from the group consisting of 1,4-bis(3,4-dihydroxphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dihydroxyphenyl)butane; 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-diethoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropoxyphenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)-4-(3,4,5-trihydroxyphenyl)butane; 1,4-bis(3,4-diacetoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropionyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dibutyroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-divaleroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipivaloyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dineopentylcarboxylphenyl)-2,3-dimethylbutane; dihydroxyphenyl)-4-phenylbutane; 1-(3,4-dihydroxyphenyl)-4-(2,5-dihydroxyphenyl)butane, nordihydroguaiaretic acid (NDGA), tetra-O-methyl NDGA; tetraglycinyl NDGA; tetra-dimethylglycinyl NDGA or a salt thereof; or tri-O-methyl NDGA; nordihydroguaiaretic acid tetrapivalate; nordihydroguaiaretic acid tetrapropionate and all optical configurations thereof. 
     
     
         36 . The method of  claim 34 , wherein the catecholic butane is administered in an amount selected from the group consisting of about 5 mg/kg to about 375 mg/kg per dose; about 5 mg/kg to about 250 mg/kg per dose; about 5 mg/kg to about 200 mg/kg per dose; about 5 mg/kg to about 150 mg/kg per dose; about 5 mg/kg to about 100 mg/kg per dose; about 5 mg/kg to about 75 mg/kg per dose; and about 5 mg/kg to about 50 mg/kg per dose. 
     
     
         37 . The method of  claim 34 , wherein the catecholic butane is administered in an amount selected from the group consisting of from about 1,500 mg per day to about 2,500 mg per day; from about 1,800 mg per day to about 2,300 mg per day; and about 2,000 mg per day. 
     
     
         38 . The method of  claim 34 , wherein the catecholic butane is administered more frequently than once every 6 days for a period of time, or more frequently than once every 2 days for a period of time. 
     
     
         39 . The method of  claim 30 , further comprising administering one or more additional anti cancer agents. 
     
     
         40 . The method of  claim 39 , wherein said one or more additional anti-cancer agents is selected from the group consisting of EGFR inhibitors, IGF-1R inhibitors, DNA damaging agents, topoisomerase inhibitors and mitotic inhibitors.