Treatment of cancers with acquired resistance to kit inhibitors

Abstract

The present invention provides compositions and methods for treating cancers which have acquired resistance to a KIT inhibitor by administering effective amounts of DAST.

1 - 29 . (canceled) 
     
     
         30 . A method to determine the ability of DAST to treat a hyper-proliferative disease, such as cancer, with acquired resistance to a KIT inhibitor, comprising culturing cancer cells in the presence of DAST, wherein DAST is 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide or a polymorph, hydrate, pharmaceutically acceptable salt, metabolite, prodrug or solvate thereof, or a combination thereof. 
     
     
         31 . A method according to  claim 30 , wherein the cells express a double-mutation. 
     
     
         32 . A method according to  claim 30 , wherein the cells express the constitutively active KIT polypeptide. 
     
     
         33 . A method to suggest cancer treatment for a patient, comprising taking a cancer cell sample from said patient, test the cells in the method according to  claim 30 , and if cells die as a result of the test, determine that the cells are sensitive to DAST and thus useful in treating the patient who has acquired resistance to the KIT inhibitor. 
     
     
         34 . A method of determining whether to treat a subject having cancer with DAST, comprising determining the presence of a mutation in a KIT gene, wherein said mutation is an activating and/or KIT-inhibitor resistance mutation, wherein DAST is 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide or a polymorph, hydrate, pharmaceutically acceptable salt, metabolite, prodrug or solvate thereof, or a combination thereof. 
     
     
         35 . A method according to  claim 34 , further comprising suggesting the administration of DAST to the subject. 
     
     
         36 . A method according to  claim 34 , further comprising the administration of DAST to the subject. 
     
     
         37 . A method for enhancing a patient's quality of life who has cancer, which patient has a secondary mutation that is one or more of
 i) deletion of amino acid residues 557-558;   ii) deletion of amino acid residues 551-555;   iii) deletion of amino acid residues 550-558;   iv) deletion of amino acid residues 559-560;   v) deletion of amino acid residues 557-561;   vi) deletion of amino acid residues 554-558;   vii) deletion of amino acid residues 552-557;   viii) mutations at residue 559, including V559D, V559A, or V559G;   ix) mutations at residue 560, including V560D, V560E, or V560G;   x) W557S, alone, or in combination with a deletion of amino acids 552-556;   xi) mutations at amino acid residue 557, including W557R; and   xii) mutations at amino acid residue 576, including L576P,   
       comprising administering to said patient an effective amount of DAST, wherein DAST is 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide or a polymorph, hydrate, pharmaceutically acceptable salt, metabolite, prodrug or solvate thereof, or a combination thereof. 
     
     
         38 . A method according to  claim 37 , wherein the DAST is in the form of a solid dispersion. 
     
     
         39 . A method according to  claim 37 , wherein the DAST is administered with sugar. 
     
     
         40 . A method according to  claim 37 , wherein the DAST is in a preparation that is colored to provide a palatable preparation. 
     
     
         41 . A method according to  claim 37 , wherein the cancer is in the form of an unspecified adult solid tumor. 
     
     
         42 . A method according to  claim 37 , wherein the DAST is in a preparation that has been formulated with ethanol and is given orally. 
     
     
         43 . A method according to  claim 37 , wherein to reduce undesirable side effects, the DAST has been modified with one or more labile functional groups. 
     
     
         44 . A method according to  claim 37 , wherein the DAST has been formulated for controlled release, where release of the active ingredient is regulated or modulated to achieve a desired rate of delivery into the systemic circulation, preferably rapid or fast release. 
     
     
         45 . Use of DAST according to  claim 37 , wherein the cancer was initially sensitive to a derivative of imatinib mesylate and acquired resistance to a derivative of imatinib mesylate, other than a salt of imatinib mesylate, and wherein an effective amount of DAST is administered to the patient. 
     
     
         46 . Use according to  claim 45 , further comprising additionally administering imatinib mesylate, a derivative of imatinib mesylate, or a salt of imatinib mesylate. 
     
     
         47 . DAST, which is used according to  claim 37 . 
     
     
         48 . DAST, which is used together with imatinib mesylate, a derivative of imatinib mesylate, or a salt of imatinib mesylate as recited in  claim 45 .