Methods for treating chemoresistant cancer-initiating cells

Abstract

The disclosure provides methods of treating cancer by selectively inhibiting p-S552-β-catenin, p-T217-β-catenin, T332-β-catenin, and/or p-S675-β-catenin production and/or activity. Such methods also and/or limit cancer-initiating cells.

1 . A method of treating cancer, comprising administering to a subject in need thereof a pharmaceutically active molecule that is capable of selectively inhibiting p-S 552 -β-catenin, p-T 217 -β-catenin, p-T 332 -β-catenin, and/or p-S 675 -β-catenin production and/or activity, wherein the pharmaceutically active molecule is administered in an amount effective to reduce and/or limit cancer-initiating cells. 
     
     
         2 . The method of  claim 1  wherein the cancer is resistant to traditional treatment. 
     
     
         3 . The method of  claim 2 , wherein the traditional treatment is radiation therapy, chemotherapy, immunotherapy, or any combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the cancer is selected from the group consisting of leukemia, lymphoma, prostate cancer, breast cancer, endometrial cancer, gastrointestinal cancer, lung cancer, melanoma, sarcoma, neuroblastoma, mesothelioma, testicular cancer, thyroid cancer, ovarian cancer, uterine cancer, pancreatic cancer, liver cancer, and Wilms' Tumor. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the pharmaceutically active molecule is administered in a low dose. 
     
     
         7 . The method of  claim 6 , wherein the low dose is about ⅕ to 1/50 of the clinical dose of the pharmaceutically active molecule when dosed for chemotherapy. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutically active molecule is administered in a nanoparticle formulation. 
     
     
         9 - 13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the pharmaceutically active molecule is administered in one or more nanoparticle compositions comprising a block copolymer in a core/shell form, wherein the block copolymer comprises:
 a first block, which is of formula:   
       
         
           
           
               
               
           
         
         and a second block, which is of formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         m and n are independently an integer about 3 to about 500; 
         A is independently selected from polynorbonene, polycyclopentene, polycyclooctene, polyacrylate, polymethacrylate, a polysiloxane, polylactide, polycaprolactone, polyester, and polypeptide; 
         R 1  is a steroid moiety optionally comprising a linker; and 
         R2 is a polyalkylene oxide moiety. 
       
     
     
         15 - 21 . (canceled) 
     
     
         22 . The method of  claim 14 , comprising the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         x is an integer between about 3 and about 100; 
         m is an integer between about 5 and about 200; and 
         n is an integer between about 5 and about 100. 
       
     
     
         23 - 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the pharmaceutically active molecule is administered in one or more nanoparticle compositions comprising a block copolymer in a core/shell form, wherein the block copolymer comprises:
 a first block, which is of formula:   
       
         
           
           
               
               
           
         
         and a second block, which is of formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         q is an integer about 3 to about 500; 
         A 1  is independently selected from polyacrylate, polymethacrylate, polynorbonene, polycyclopentene, polycyclooctene, polysiloxane, polylactide, polycaprolactone,polyester, and polypeptide; 
         R 11  is a steroid moiety optionally comprising a linker R 14 ; 
         R 12  is polyalkylene oxide, polyester, or polypeptide moiety; and 
         R 13  is a disulfide linker moiety. 
       
     
     
         28 - 32 . (canceled) 
     
     
         33 . The method of  claim 27 , wherein the first block is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of  claim 27 , wherein R 13  is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 - 40 . (canceled) 
     
     
         41 . The method of  claim 27 , comprising the structure: 
       
         
           
           
               
               
           
         
         wherein 
         wherein X is a trithiocarbonate, dithiocarbamate, or dithioester; 
         q is an integer between about 5 and about 200; and 
         r is an integer between about 5 and about 100. 
       
     
     
         42 - 44 . (canceled) 
     
     
         45 . The method of  claim 8 , wherein the pharmaceutically active molecule is hydrophobic. 
     
     
         46 . The method of  claim 8 , wherein the pharmaceutically active molecule is anthracycline. 
     
     
         47 . The method of  claim 8 , wherein the pharmaceutically active molecule is doxorubicin, daunorubicin, vincristine, epirubicin, idarubicin, valrubicin, mitoxantrone, paclitaxel, docetaxel, cisplatin, camptothecin, irinotecan, 5-fluorouracil, methotrexate, or dexamethasone. 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . The method of  claim 8 , comprising administering a combination of two different nanoparticle compositions. 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 50 , wherein a second nanoparticle composition comprises the hydrophobic pharmaceutically active molecule selected from the group consisting of daunorubicin, vincristine, epirubicin, idarubicin, valrubicin, mitoxantrone, paclitaxel, docetaxel, cisplatin, camptothecin, irinotecan, 5-fluorouracil, methotrexate, and dexamethasone. 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 8 , wherein the nanoparticle composition further comprises one or more metal nanoparticles or quantum dots. 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 8 , wherein the nanoparticle is between about 5 and about 500 nm in diameter. 
     
     
         58 . (canceled) 
     
     
         59 . (canceled)