2-acetylnaphtho[2,3-b]furan -4,9-dione for use on treating cancer

Abstract

The invention provides naphthofuran compounds, polymorphs of naphthofuran compounds, naphthofuran compounds in particle form, purified compositions that contain one or more naphthofuran compounds, purified compositions that contain one or more naphthofuran compounds in particle form, and methods of using these naphthofuran compounds, polymorphs, purified compositions and/or particle forms to treat subjects in need thereof.

1 . A method of treating a cancer in a human subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the compound is administered to the subject at a total daily dose in a range from about 80 mg to about 2000 mg. 
     
     
         2 - 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the interval between administrations of the compound is selected from the group consisting of at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours and at least about 16 hours, and wherein the compound is administered to the subject at a dose selected from the group consisting of about 80 mg BID, about 160 mg BID, about 320 mg BID, about 400 mg BID, about 480 mg BID, about 500 mg BID, and about 600 mg BID. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein each dose is about 480 mg BID and the interval between administrations is about 12 hours. 
     
     
         12 - 22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the cancer is selected from the group consisting of gastric cancer, gastroesophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck cancer, and melanoma. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the cancer is refractory, recurrent, or metastatic. 
     
     
         26 - 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the cancer is associated with nuclear β-catenin overexpression. 
     
     
         31 . The method of  claim 1 , the method further comprising detecting nuclear β-catenin expression in a patient's tissue, where such nuclear β-catenin expression is used as a biomarker for patient selection. 
     
     
         32 . A method of curative or prophylactic cancer treatment, the method comprising the steps of:
 (a) administering to a subject in need of a curative or prophylactic cancer treatment a dosage of a first agent having the structure   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and
 (b) administering to the subject a dosage of an antimitotic agent or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the antimitotic agent is selected from the group consisting of paclitaxel (Abraxane/Taxol), docetaxel (taxotere), BMS-275183, xyotax, tocosal, vinorlebine, vincristine, vinblastine, vindesine, vinzolidine, etoposide (VP-16), teniposide (VM-26), ixabepilone, larotaxel, ortataxel, tesetaxel, and ispinesib. 
 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 32 , wherein the antimitotic agent comprises paclitaxel (Abraxane/Taxol). 
     
     
         36 . The method of  claim 32 , wherein the cancer is selected from the group consisting of gastric cancer, gastroesophageal junction cancer, and esophageal cancer. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 32 , wherein the cancer is refractory, recurrent, or metastatic. 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 32 , the method further comprising detecting a level of phosphorylated STAT3 (p-STAT3) in a patient tissue, where the level of p-STAT3 is used as a biomarker for patient selection. 
     
     
         42 . The method of  claim 32 , wherein the cancer is associated with overexpression of nuclear β-catenin. 
     
     
         43 . The method of  claim 32 , the method further comprising detecting a nuclear β-catenin expression in a patient's tissue, where nuclear β-catenin expression is used as a biomarker for patient selection. 
     
     
         44 - 49 . (canceled) 
     
     
         50 . The method of  claim 70  wherein the human subject has a significant β-catenin expression in cell nucleus. 
     
     
         51 . The method of  claim 50 , wherein the cancer is selected from the group consisting of gastric and gastroesophageal adenocarcinoma, esophageal adenocarcinoma, colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck cancer, melanoma, and adrenocorticoid carcinoma. 
     
     
         52 . The method of  claim 50 , wherein the cancer is colorectal adenocarcinoma. 
     
     
         53 . The method of  claim 50 , wherein the cancer is refractory, recurrent, or metastatic. 
     
     
         54 - 63 . (canceled) 
     
     
         64 . The pharmaceutical composition of  claim 115 , 
       wherein said polyoxylglycerides of which HLB is more than 10 is Gelucire (lauroyl polyoxylglycerides), and said polyoxylglycerides of which HLB is less than 10 is Labrafil (linoleoyl polyoxylglycerides). 
     
     
         65 . The pharmaceutical composition of  claim 64 , further consisting of, by weight, about 27.18% in the active ingredient, about 0.27% in the surfactant, about 14.51% in Gelucire, and about 58.04% in Labrafil. 
     
     
         66 . The pharmaceutical composition of  claim 64 , further consisting of about 125 mg of the active ingredient, about 1.2 mg of the surfactant, about 66.8 mg of Gelucire, and about 267 mg of Labrafil. 
     
     
         67 . The pharmaceutical composition of  claim 64 , further consisting of about 80 mg of the active ingredient, about 0.8 mg of the surfactant, about 42.7 mg of Gelucire, and about 170.9 mg of Labrafil. 
     
     
         68 . (canceled) 
     
     
         69 . (canceled) 
     
     
         70 . The method of  claim 1  wherein the human subject has
 a level and/or subcellular localization of one or more cancer stemness markers selected from phosphorylated STAT3 (p-STAT3), β-catenin, and NANOG is above a benchmark level. 
 
     
     
         71 . The method of  claim 70 , wherein the cancer is selected from the group consisting of colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck cancer, melanoma, gastric/gastroesophageal adenocarcinoma, esophageal adenocarcinoma, and adrenocorticoid carcinoma. 
     
     
         72 . The method of  claim 70 , wherein the cancer is colorectal adenocarcinoma. 
     
     
         73 . The method of  claim 70 , wherein the cancer is refractory, recurrent, or metastatic. 
     
     
         74 - 112 . (canceled) 
     
     
         113 . A pharmaceutical composition, comprising:
 (a) a therapeutically effective amount of an active ingredient having the structure   
       
         
           
           
               
               
           
         
         (b) polyoxylglycerides of which HLB is more than 10; and 
         (c) polyoxylglycerides of which HLB is less than 10. 
       
     
     
         114 . The pharmaceutical composition according to  claim 113 , wherein the composition further comprises a surfactant. 
     
     
         115 . The pharmaceutical composition according to  claim 114 , wherein: the polyoxylglycerides of which HLB is more than 10 is selected from the group consisting of lauroyl polyoxylglycerides and stearoyl polyoxylglycerides; the polyoxylglycerides of which HLB is less than 10 is linoleoyl polyoxylglycerides; and the surfactant is sodium lauryl sulfate (SLS) or sodium dodecyl sulfate. 
     
     
         116 - 119 . (canceled)