Therapy for kinase-dependent malignancies

Abstract

A pharmaceutically acceptable composition and method of therapy for a kinase-dependent malignancy in a patient in need of such therapy is provided. The composition contains, as the only active agents, the combination of (a) an inhibitor of c-Fos, (b) an inhibitor of Dusp-1, and (c) an inhibitor of a tyrosine kinase. The composition is administered to the patient in a dosing regimen for a period sufficient to provide therapy for kinase-dependent malignancy. Also provided is a method to eradicate leukemia initiating cells (LIC) or cancer stem cells (CSC) in a patient being treated with a tyrosine kinase inhibitor.

What is claimed is: 
     
         1 . A pharmaceutically acceptable composition comprising at least one biocompatible excipient and, as the only active agents, (a) a c-Fos inhibitor, (b) a Dusp-1 inhibitor, and (c) at least one oncogenic kinase inhibitor, where the oncogenic kinase is selected from the group consisting of BCR-ABL, BTK, FLT3, MET, KIT, JAK2, MEK, EGFR, PDGFR, ALK, HER2, B-Raf, FGFR2, RAF, PI3K, and combinations thereof. 
     
     
         2 . The pharmaceutically acceptable composition of  claim 1  wherein,
 (a) the c-Fos inhibitor is selected from the group consisting of curcumin, difluorinated curcumin (DFC), [3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid] (T5224), nordihydroguaiaretic acid (NOGA), dihydroguaiaretic acid (DHGA), and [(E,E,Z,E)-3-methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid (SR11302); 
 (b) the Dusp-1 inhibitor is selected from the group consisting of (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI—also known as NSC 150117), TP1-2, TP1-3, and triptolide; and 
 (c) the tyrosine kinase inhibitor is selected from the group consisting of lmatinib, Dasatinib, Ponatinib or Nilotinib when the oncogenic kinase is BCR-ABL; lbrutinib when the oncogenic kinase is BTK; Ruxolitinib, Crizotinib, or Quizartinib when the oncogenic kinase is one of FL T3, MET, KIT, or JAK2; Ruxolitinib or Trametinib when the oncogenic kinase is JAK2 or MEK; Gefitinib or Axitinib when the oncogenic kinase is one of EGFR, PDGFR, or ALK; Gefitinib, Axitinib, or dasatinib when the oncogenic kinase is one of EGFR or PDGFR; Gefitinib or Axitinib when the oncogenic kinase is one of HER2 or EGFR; Vemurafenib or Sorafenib when the oncogenic kinase is one of B-Raf or MEK; Crizotinib or Dasatinib when the oncogenic kinase is one of MET, FGFR2, or HER2; Ceritinib, Alectinib or Crizotinib when the oncogenic kinase is one of MET, FGFR2, or HER2; Ceritinib, Alectinib or Crizotinib when the oncogenic kinase is one of ALK, KIT, or FGFR; and Vemurafenib, Sorafenib or ldelalisib when the oncogenic kinase is one of RAF or PI3K. 
 
     
     
         3 . (canceled) 
     
     
         4 . A method of treating a kinase-dependent malignancy in a patient, the method comprising administering to the patient in need thereof a composition containing at least one biocompatible excipient and, as the only active agents, a combination of
 (a) an inhibitor of c-Fos resulting in inhibition of c-Fos,   (b) an inhibitor of Dusp-1 resulting in inhibition of Dusp-1, and   (c) at least one inhibitor of an oncogenic kinase resulting in inhibition of the oncogenic kinase, wherein the composition is administered to the patient in a dosing regimen for a period sufficient to provide treatment for the kinase-dependent malignancy in the patient in need thereof.   
     
     
         5 . The method of  claim 4 , wherein
 (a) the c-Fos inhibitor is selected from the group consisting of curcumin, difluorinated curcumin (DFC), [3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid] (T5224), nordihydroguaiaretic acid (NOGA), dihydroguaiaretic acid (DHGA), and [(E,E,Z,E)-3-methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4, 6,8-nonatetraenoic acid (SR11302); and   (b) the Dusp-1 inhibitor is selected from the group consisting of (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI—also known as NSC 150117), TP1-2, TP1-3, and triptolide.   
     
     
         6 . The method of  claim 4 , wherein the kinase-dependent malignancy is:
 Chronic myeloid leukemia (CIVIL) and the at least one inhibitor is lmatinib, Dasatinib, Ponatinib and/or Nilotinib;   Chronic lymphocytic leukemia (CLL) and the at least one inhibitor is lbrutinib;   Acute myeloid leukemia (AML) and the at least one inhibitor is Ruxolitinib, Crizotinib, and/or Quizartinib;   Myeloproliferative Neoplasm (MPN) and the at least one inhibitor is Ruxolitinib and/or Trametinib;   lung cancer and the at least one inhibitor is Gefitinib and/or Axitinib;   brain tumor and the at least one inhibitor is Gefitinib, Axitinib, and/or Dasatinib;   breast cancer and the at least one inhibitor is Gefitinib and/or Axitinib;   bladder carcinoma and the at least one inhibitor is Gefitinib and/or Axitinib;   melanoma and the at least one inhibitor is Vemurafenib and/or Sorafenib;   pancreatic cancer and the at least one inhibitor is Crizotinib and/or Dasatinib;   colon cancer and the at least one inhibitor is Ceritinib, Alectinib and/or Crizotinib; and   prostate cancer and the at least one inhibitor is Vemurafenib, Sorafenib and/or ldelalisib.   
     
     
         7 . The method of  claim 4 , wherein the treatment is curative. 
     
     
         8 . A method to eradicate leukemia initiating cells (LIC) or cancer stem cells (CSC) in a patient being treated with a tyrosine kinase inhibitor (TKI), the method comprising administering to the patient in need thereof a composition containing at least one biocompatible excipient and a combination of
 (a) an inhibitor of c-Fos resulting in inhibition of c-Fos, and   (b) an inhibitor of Dusp-1 resulting in inhibition of Dusp-1,   
       the composition administered to the patient in a dosing regimen for a period sufficient to eradicate the LIC or CSC cells.