Compositions and Methods of Treating Tumors

Abstract

Methods of treating an individual who has an erbB protein mediated tumor is disclosed. Methods of preventing erbB protein mediated tumors in an individual are disclosed. The methods comprise administering to the individual a nucleic acid molecule that encodes a protein that dimerizes with an erbB protein and that is deficient in tyrosine kinase activity. Composition that comprise such nucleic acid molecules including pharmaceutical compositions are disclosed.

1 . A method of treating an individual who has an erbB-protein mediated tumor which method comprises the steps of:
 (a) administering to said individual two or more antibodies that recognize distinct erbB epitopes and inhibit formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell, said inhibition having a cytostatic effect on said tumor cell; and   (b) thereafter exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         2 . The method of  claim 1  wherein said erbB-protein mediated tumor is a p185-mediated tumor and/or an EGFR-mediated tumor. 
     
     
         3 . The method of  claim 1  wherein said erbB-protein is comprises a p185, mutant p185, EGFR, or mutant EGFR protein. 
     
     
         4 . The method of  claim 1  wherein said antibodies interact with said erbB protein in a tumor cell to alter said erbB protein sufficient to result in a decreased propensity of said erbB protein to dimerize with another erbB protein. 
     
     
         5 . The method of  claim 1  wherein said antibodies inhibit ligand independent formation of erbB protein dimers. 
     
     
         6 . The method of  claim 1  wherein said antibodies competitively inhibit formation of erbB protein dimers and prevent elevated tyrosine kinase activity. 
     
     
         7 . A method of treating an individual who has a tumor, wherein said tumor is characterized by tumor cells that have multimeric receptor ensembles which provide tyrosine kinase activity associated with a transformed phenotype, wherein said multimeric receptor ensembles comprise:
 (i) erbB homodimers that are EGFR homodimers, mutant EGFR homodimers p185 homodimers, or mutant p185 homodimers; or   (ii) erbB heterodimers that are p185/EGFR heterodimers, p185/mutant EGFR heterodimers, mutant p185/EGFR heterodimers, mutant p185/mutant EGFR heterodimers, mutant p185/p185 heterodimers; p185/erbB3 heterodimers, p185/erbB4 heterodimers or EGFR/mutant EGFR heterodimers; and which method comprises the steps of:   (a) administering to said individual two or more antibodies that recognize distinct erbB epitopes and disrupt kinase activity associated with said multimeric receptor ensemble, said disruption having a cytostatic effect on said tumor cell; and   (b) thereafter exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         8 . The method of  claim 7  wherein said antibodies inhibit formation of a p185 homodimer. 
     
     
         9 . The method of  claim 7  wherein said antibodies inhibit formation of a EGFR homodimer. 
     
     
         10 . The method of  claim 7  wherein said antibodies inhibit formation of a heterodimer of p185 and EGFR. 
     
     
         11 . The method of  claim 7  wherein said antibodies disrupt ligand independent kinase activity associated with said multimeric receptor ensemble. 
     
     
         12 . A method of treating an individual who has a tumor, wherein said tumor is characterized by tumor cells that comprise EGFR, said method comprising the steps of:
 (a) administering to said individual, two or more antibodies that recognize distinct erbB epitopes and disrupt kinase activity mediated by EGFR, said disruption having a cytostatic effect on said tumor cells; and   (b) thereafter exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         13 . The method of  claim 12  wherein said antibodies disrupt ligand independent kinase activity mediated by EGFR. 
     
     
         14 . The method of  claim 12  wherein said tumor is a p185-mediated tumor and/or an EGFR-mediated tumor. 
     
     
         15 . The method of  claim 12  wherein said tumor cell comprises a p185, mutant p185, or mutant EGFR protein. 
     
     
         16 . The method of  claim 12  wherein said antibodies interact with said erbB epitopes in a tumor cell to alter said erbB protein sufficient to result in a decreased propensity of said erbB protein to dimerize with another erbB protein. 
     
     
         17 . The method of  claim 12  wherein said antibodies competitively inhibit formation of erbB protein dimers and prevent elevated tyrosine kinase activity. 
     
     
         18 . A method for inhibiting proliferation of a tumor cell, said tumor cell being from an erbB-protein mediated tumor, which method comprises the steps of:
 (a) contacting said cell with two or more antibodies that recognize distinct erbB epitopes and inhibit formation of an erbB protein dimer, which erbB protein dimer produces tyrosine kinase activity in said tumor cell and wherein inhibiting the formation of said erbB protein dimer has a cytostatic effect said tumor cell; and   (b) thereafter exposing said tumor cell to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         19 . The method of  claim 18  wherein said antibodies inhibit formation of a p185 homodimer. 
     
     
         20 . The method of  claim 18  wherein said antibodies inhibit formation of a EGFR homodimer. 
     
     
         21 . The method of  claim 18  wherein said antibodies inhibit formation of a heterodimer of p185 and EGFR. 
     
     
         22 . The method of  claim 18  wherein said antibodies inhibit ligand independent formation of said erbB protein dimer. 
     
     
         23 . A method for inhibiting proliferation of a tumor cell, said tumor cell being from an erbB-protein mediated tumor, which method comprises the steps of:
 (a) contacting said cell with two or more antibodies that recognize distinct erbB epitopes and disrupt erbB kinase activity said disruption having a cytostatic effect on said tumor cell; and   (b) thereafter exposing said tumor cell to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         24 . The method of  claim 23  wherein said antibodies inhibit kinase activity mediated by an EGFR homodimer. 
     
     
         25 . The method of  claim 23  wherein said antibodies inhibit kinase activity mediated by a p185 homodimer. 
     
     
         26 . The method of  claim 23  wherein said antibodies inhibit kinase activity mediated by a heterodimer of p185 and EGFR. 
     
     
         27 . The method of  claim 23  wherein said antibodies inhibit formation of a p185 homodimer. 
     
     
         28 . The method of  claim 23  wherein said antibodies inhibit formation of a EGFR homodimer. 
     
     
         29 . The method of  claim 23  wherein said antibodies inhibit formation of a heterodimer of p185 and EGFR. 
     
     
         30 . The method of  claim 23  wherein said antibodies disrupt ligand independent erbB kinase activity. 
     
     
         31 . A method of treating an individual who has an erbB-protein mediated tumor which method comprises the steps of:
 (a) administering to said individual a non-proteinaceous kinase inhibitor that binds erbB protein and inhibits elevated tyrosine kinase activity in a tumor cell; and   (b) thereafter exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         32 . The method of  claim 31  wherein said non-proteinaceous kinase inhibitor prevents ATP from binding a critical lysine residue in an ATP binding domain of said erbB protein 
     
     
         33 . The method of  claim 31  wherein said inhibition has a cytostatic effect on said tumor cell. 
     
     
         34 . The method of  claim 31  wherein said erbB-protein mediated tumor is a p185-mediated tumor and/or an EGFR-mediated tumor. 
     
     
         35 . The method of  claim 31  wherein said erbB-protein comprises a p185, mutant p185, EGFR, or mutant EGFR protein. 
     
     
         36 . The method of  claim 31  wherein said non-proteinaceous kinase inhibitor interacts with said erbB protein in a tumor cell to alter said erbB protein sufficient to result in a decreased propensity of said erbB protein to dimerize with another erbB protein. 
     
     
         37 . The method of  claim 31  wherein said non-proteinaceous kinase inhibitor inhibits ligand independent formation of erbB protein dimers. 
     
     
         38 . The method of  claim 31  wherein said non-proteinaceous kinase inhibitor competitively inhibits formation of erbB protein dimers and prevents elevated tyrosine kinase activity. 
     
     
         39 . A method of treating an individual who has an erbB-protein mediated tumor which method comprises the steps of:
 (a) administering to said individual a non-proteinaceous kinase inhibitor that binds erbB protein in combination with one or more antibodies that that recognize distinct erbB epitopes, wherein both said kinase inhibitor and antibodies inhibit elevated tyrosine kinase activity in a tumor cell; and   (b) thereafter exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or anti-cancer chemotherapeutic.   
     
     
         40 . The method of  claim 39  wherein said erbB-protein mediated tumor is a p185-mediated tumor and/or an EGFR-mediated tumor. 
     
     
         41 . The method of  claim 39  wherein said erbB-protein comprises a p185, mutant p185, EGFR, or mutant EGFR protein. 
     
     
         42 . The method of  claim 39  said non-proteinaceous kinase inhibitor and/or said antibodies interact with said erbB protein in a tumor cell to alter said erbB protein sufficient to result in a decreased propensity of said erbB protein to dimerize with another erbB protein. 
     
     
         43 . The method of  claim 39  said non-proteinaceous kinase inhibitor and/or said antibodies inhibit ligand independent formation of erbB protein dimers. 
     
     
         44 . The method of  claim 39  said non-proteinaceous kinase inhibitor and/or said antibodies competitively inhibit formation of erbB protein dimers and prevent elevated tyrosine kinase activity. 
     
     
         45 . The method of  claim 39  wherein said non-proteinaceous kinase inhibitor prevents ATP from binding a critical lysine residue in an ATP binding domain of said erbB protein.