Treatment of h-ras-driven tumors

Abstract

The present disclosure describes a compositions and methods for treatment of Hras-driven cancers. Administration of a farnesyltransferase inhibitor, for example, tipifarnib, alone or in combination with a MEK inhibitor can reduce tumor size and tumor growth in cancers such as poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC)

We claim: 
     
         1 . A method for reducing tumor burden in a subject with head and neck squamous cell carcinoma (HNSCC) comprising administering to the subject a therapeutically effective amount of a farnesyltransferase inhibitor (FTI), wherein the HNSCC comprises a constitutively activating mutation of Hras. 
     
     
         2 . The method of  claim 1 , wherein the farnesyltransferase inhibitor (FTI) is administered in combination with a MEK inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the FTI is selected from the group consisting of tipifarnib and lonafarnib. 
     
     
         4 . The method of  claim 1 , wherein the FTI is tipifarnib. 
     
     
         5 . The method of  claim 2 , wherein said MEK inhibitor is selected from the group consisting of AZD8330, Refametinib, Cobimetinib, E6201, MEK162, PD0325901, pimasertib, RO4987655, RO5126766, selumetinib, TAK-733, trametinib, GDC-0623, and WX-554. 
     
     
         6 . The method of  claim 1 , wherein the constitutively activating mutation comprises a mutation/substitution at codon 12, 13 or 61 of Hras. 
     
     
         7 . The method of  claim 1 , wherein the constitutively activating mutation is Hras G12V. 
     
     
         8 . The method of  claim 1 , wherein the constitutively activating mutation is Hras Q61L. 
     
     
         9 . The method of  claim 1 , wherein tipifarnib is administered at a dose of 25-300 mg twice a day (bid). 
     
     
         10 . The method of  claim 1 , wherein tipifarnib is administered at a dose of 50-100 mg twice a day (bid). 
     
     
         11 . A method for the treatment of a patient determined to have a head and neck squamous cell carcinoma (HNSCC) associated with a constitutively activating mutation of Hras, the method comprising administering to the patient a therapeutically effective amount of a farnesyltransferase inhibitor (FTI). 
     
     
         12 . The method of  claim 11 , further comprising detecting a constitutively activating mutation of Hras in a DNA or RNA sample from a cancer cell from the patient prior to administering the FTI. 
     
     
         13 . The method of  claim 11 , wherein the FTI is administered in combination with a MEK inhibitor. 
     
     
         14 . The method of  claim 11 , wherein the constitutively activating mutation comprises a mutation/substitution at codon 12, 13 or 61 of Hras. 
     
     
         15 . The method of  claim 11 , wherein the constitutively activating mutation is Hras G12V. 
     
     
         16 . The method of  claim 11 , wherein the constitutively activating mutation is Hras Q61L. 
     
     
         17 . A method for the treatment of a head and neck squamous cell carcinoma (HNSCC) associated with a constitutively activating mutation of Hras in a patient in need thereof, comprising administering to the patient a therapeutically effect amount of tipifarnib and selumetinib. 
     
     
         18 . The method of  claim 17 , wherein the constitutively activating mutation comprises a mutation/substitution at codon 12, 13 or 61 of Hras. 
     
     
         19 . The method of  claim 17 , wherein the constitutively activating mutation is Hras G12V. 
     
     
         20 . The method of  claim 17 , wherein the constitutively activating mutation is Hras Q61L.