Pharmaceutical compositions and methods for treating cancer and biomarkers for drug screening

Abstract

A pharmaceutical composition is provided which includes sorafenib and GW5074. This combination therapy inhibits cancer cell growth via c-Raf-PP2A-DAPK signaling transduction pathway in either an in vitro or pre-clinical animal model for orthotopic spontaneous kidney cancer which simulates clinical symptoms. Formation of the bond between c-Raf and GW5074 leads to conformational change which consequently increases the affinity between sorafenib and c-Raf. Binding with the specific drug target facilitates serine 308 dephosphorylation of DAPK by PP2A and induces necrosis in cancer cells. Serine 308 of DAPK protein may also be used as a biomarker for drug screening. A novel pharmaceutical composition is provided which includes sorafenib and GW5074, a protein complex target consisting of c-Raf and DAPK for drug designing, as well as biomarkers including c-Raf protein, DAPK protein and phosphorylation status of DAPK for drug screening.

1 . A pharmaceutical composition used for treating cancer, comprising sorafenib and GW5074 (3-(3,5-Dibromo-4-hydroxy-benzylidene)-5-iodo-1,3-dihydro-indol-2-one). 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the sorafenib and GW5074 are administered separately or concurrently. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the cancer comprises kidney cancer, prostate cancer, breast cancer, lung cancer, cervical carcinoma, oral cancer, glioma, urothelial call carcinoma, or melanoma. 
     
     
         4 . The pharmaceutical composition of  claim 1 , further comprising pharmaceutically acceptable salts or vehicles. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the vehicles include excipients, diluents, thickeners, fillers, binders, disintegrants, lubricants, oil or non-oil agents, surfactants, suspending agents, gelling agents, adjuvants, preservatives, antioxidants, stabilizers, coloring agents, or spices thereof. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the composition is given by oral administration, immersion, injection, topical applications, or patch administration. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the composition GW5074 binds to c-Raf protein (SEQ ID NO: 1) and induces conformational changes in c-Raf, which consequently increases the binding affinity of sorafenib to the altered c-Raf protein and facilitates dissociation of c-Raf from a DAPK protein complex. 
     
     
         8 - 17 . (canceled)