Method for treating diseases associated with abnormal kinase activity

Abstract

Methods are provided for treating diseases associated with abnormal activity of kinases. The method comprises: administering a DNA methylation inhibitor to the patient in therapeutically effective amount; and administering a kinase inhibitor to the patient in therapeutically effective amount, such that the in vivo activity of the kinase is reduced relative to that prior to the treatment. The method can be used to treat cancer associated with abnormal activity of kinases such as phosphatidylinositol 3′-kinase (PI3K), protein kinases including serine/threonine kinases such as Raf kinases, protein kinase kinases such as MEK, and tyrosine kinases such as those in the epidermal growth factor receptor family (EGFR), platelet-derived growth factor receptor family (PDGFR), vascular endothelial growth factor receptor (VEGFR) family, nerve growth factor receptor family (NGFR), fibroblast growth factor receptor family (FGFR) insulin receptor family, ephrin receptor family, Met family, Ror family, c-kit family, Src family, Fes family, JAK family, Fak family, Btk family, Syk/ZAP-70 family, and Abl family.

1 . A method for treating a patient having a condition associated with abnormal tyrosine kinase activity comprising: 
 administering a DNA methylation inhibitor to the patient in therapeutically effective amount; and    administering an inhibitor of a vascular endothelial growth factor receptor (VEGFR) to the patient in therapeutically effective amount, such that the in vivo activity of the VEGFR is reduced relative to that prior to the treatment.    
     
     
         2 . The method of  claim 1 , wherein the condition is selected from the group consisting of inflammation, benign tumors, malignant tumors, leukemia, asthma, allergy-associated chronic rhinitis, autoimmune diseases and mastolocytosis.  
     
     
         3 . The method of  claim 1 , wherein the DNA methylation inhibitor is a cytidine analog.  
     
     
         4 . The method of  claim 3 , wherein the cytidine analog is cytosine arabinoside.  
     
     
         5 . The method of  claim 3 , wherein the cytidine analog is decitabine.  
     
     
         6 . The method of  claim 1 , wherein the DNA methylation inhibitor is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, subcutaneously, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.  
     
     
         7 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and is administered intravenously, subcutaneously, intramuscularly, orally or via inhalation.  
     
     
         8 . The method of  claim 1 , wherein the inhibitor of the VEGFR is in a form of chemical compound, peptide, protein, enzyme, antibody, antisense fragment, antisense fragment linked to enzyme, or antisense fragment linked to peptide.  
     
     
         9 . The method of  claim 1 , wherein the inhibitor of the VEGFR is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.  
     
     
         10 . The method of  claim 1 , wherein is the inhibitor of the VEGFR inhibits activity of the VEGFR selected from the group consisting of transcriptional activity, translational activity, and post-translational activity, and differential expression of endogenenous inhibitors of the tyrosine kinase.  
     
     
         11 . The method of  claim 1 , wherein the member of the VEGFR family is selected from the group consisting of VEGFR1, VEGFR2, and VEGFR3.  
     
     
         12 . The method of  claim 1 , wherein the inhibitor of the VEGFR family is SU6668.  
     
     
         13 . The method of  claim 1 , wherein the condition is a solid or a metastasis-prone tumor.  
     
     
         14 . The method of  claim 1 , wherein the DNA methylation inhibitor and the tyrosine kinase inhibitors are co-administered in therapeutically synergistic amounts.  
     
     
         15 . The method of  claim 1 , wherein the DNA methylation inhibitor is decitabine and is administered intravenously or subcutaneously.  
     
     
         16 . The method of  claim 5 , wherein decitabine is administered to the patient via an intravenous infusion per day at a dose ranging from 1 to 100 mg/m2. (sup)  
     
     
         17 . The method of  claim 5 , wherein decitabine is administered to the patient via an intravenous infusion per day at a dose ranging from 2 to 50 mg/m2.  
     
     
         18 . The method of  claim 5 , wherein decitabine is administered to the patient via an intravenous infusion per day at a dose ranging from 5 to 20 mg/m2.  
     
     
         19 . The method of  claim 5 , wherein decitabine is administered to the patient via an intravenous infusion per day for at least 3 days per treatment cycle at a dose ranging from 1 to 100 mg/m2.  
     
     
         20 . The method of  claim 5 , wherein decitabine is administered to the patient subcutaneously at a dose ranging from 0.01 to 1 mg/Kg.  
     
     
         21 . The method of  claim 5 , wherein decitabine is administered to the patient subcutaneously at a dose ranging from 0.1 to 0.5 mg/Kg at least once a week for at least 4 weeks.  
     
     
         22 . The method of  claim 5 , wherein decitabine is administered to the patient subcutaneously at a dose ranging from 0.1 to 0.3 mg/Kg twice a week for at least 4 weeks.