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.

What is claimed is: 
     
         1 . A method of treating an individual who has an erbB protein mediated tumor comprising the steps of:
 administering to said individual a nucleic acid molecule that encodes a protein that dimerizes with said erbB protein and that is deficient in tyrosine kinase activity, and   exposing said individual to a therapeutically effective amount of anti-cancer radiation and/or administering to said individual a therapeutically effective amount of an anti-cancer chemotherapeutic.   
     
     
         2 . The method of  claim 1  wherein said erbB-protein mediated tumor is a p185-Q mediated tumor and/or an EGFR-mediated tumor. 
     
     
         3 . The method of  claim 1  wherein nucleic acid molecule is the genome of a recombinant virus. 
     
     
         4 . A method of treating an individual who has an erbB protein mediated brain tumor comprising the step of:
 administering to said individual a nucleic acid molecule that encodes a protein that dimerizes with said erbB protein and is deficient in tyrosine kinase activity.   
     
     
         5 . The method of  claim 4  wherein said erbB-protein mediated tumor is a mutant EGFR-mediated tumor. 
     
     
         6 . The method of  claim 14  wherein said individual is exposed to a therapeutically effective amount of anti-cancer radiation and/or administered a therapeutically effective amount of an anti-cancer chemotherapeutic. 
     
     
         7 . A method of inhibiting proliferation of a mutant EGFR-mediated tumor cell comprising the step of delivering to said cell a nucleic acid molecule that encodes a protein that dimerizes with mutant EGFR and is deficient in tyrosine kinase activity. 
     
     
         8 . A method of treating an individual who has an erbB protein mediated tumor comprising the steps of:
 administering to said individual a composition which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell, and   exposing said individual to a therapeutically effective amount of anti-cancer radiation.   
     
     
         9 . The method of  claim 8  wherein said erbB-protein mediated tumor is a p185-mediated tumor and/or an EGFR-mediated tumor. 
     
     
         10 . The method of  claim 8  wherein said composition that is administered to a patient comprises a compound that interacts with an erbB protein in a tumor cell to alter the erbB protein sufficient to result in a decreased propensity of it to dimerize with another erbB protein. 
     
     
         11 . The method of  claim 10  wherein said compound that interacts with an erbB protein in a tumor cell to alter the erbB protein sufficient to result in a decreased propensity of it to dimerize with another erbB protein is an antibody. 
     
     
         12 . The method of  claim 8  wherein said composition that is administered to a patient comprises a compound that competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erbB protein and prevents elevated tyrosine kinase activity. 
     
     
         13 . The method of  claim 12  wherein said compound that competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erbB protein is a peptide or an antibody. 
     
     
         14 . The method of  claim 8  wherein said composition that is administered to said tumor cell is a nucleic acid molecule that encodes a protein that competitively interacts with an erbB protein in a tumor cell to competitively inhibit dimer formation with another erbB protein. 
     
     
         15 . The method of  claim 14  wherein said protein is a mutant or truncated kinase deficient erbB protein. 
     
     
         16 . 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 kinase activity associated with a transformed phenotype, said method comprising the steps of:
 a) administering to the individual, a composition that disrupts the kinase activity associated with the multimeric receptor ensemble; and   b) exposing the individual to a therapeutic amount of gamma radiation.   
     
     
         17 . The method of  claim 16  wherein said tumor is characterized by tumor cells that have: a) erbB homodimers that are mutant EGFR homodimers or p185 N homodimers; and/or
 b) erbB heterodimers that are p185/EGFR heterodimers, p185/mutant EGFR heterodimers, p185/erbB3 heterodimers; p185/erbB4 heterodimers or EGFR/mutant EGFR heterodimers. 
 
     
     
         18 . The method of  claim 16  wherein said composition that disrupts the kinase activity associated with the multimeric receptor ensemble comprises an active agent selected from the group consisting of antibodies, peptides, and non-proteinaceous kinase inhibitors. 
     
     
         19 . The method of  claim 16  wherein said composition that disrupts the kinase activity associated with the multimeric receptor ensemble comprises an active agent that is a nucleic acid molecule that encodes a protein or peptide which interacts with a monomeric component of said ensemble to prevent said monomeric component from interacting with a 25 second monomeric component of said ensemble. 
     
     
         20 . 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 kinase activity associated with a transformed phenotype, said method comprising the steps of:
 a) administering to the individual, a peptide, non-proteinaceous compound or nucleic acid molecules that encodes a protein that disrupts the kinase activity associated with the multimeric receptor ensemble; and   b) exposing the individual to a therapeutic amount of gamma radiation and/or administering a therapeutic amount of a cytotoxic chemotherapeutic agent to said individual.   
     
     
         21 . The method of  claim 20  wherein said tumor is characterized by tumor cells that have: a) erbB homodimers that are mutant EGFR homodimers or p185 homodimers; and/or
 b) erbB heterodimers that are p185/EGFR heterodimers, 
 p185/mutant EGFR heterodimers, p185/erbB3 heterodimers; p185/erbB4 heterodimers or EGFR/mutant EGFR heterodimers. 
 
     
     
         22 . The method of  claim 20  wherein said composition that disrupts the kinase activity associated with the multimeric receptor ensemble comprises an active agent that is a nucleic acid molecule that encodes a protein or peptide which interacts with a monomeric component of said ensemble to prevent said monomeric component from interacting with a second monomeric component of said ensemble. 
     
     
         23 . A method of treating an individual who has a tumor, wherein said tumor is characterized by tumor cells that comprise an EGFR species, said method comprising the steps of:
 a) administering to the individual, a composition that disrupts kinase activity mediated by an EGFR species; and   b) exposing the individual to a therapeutic amount of gamma radiation and/or administering a therapeutic amount of a cytotoxic chemotherapeutic agent to said individual.   
     
     
         24 . The method of  claim 23  wherein said EGFR species is a mutant EGFR. 
     
     
         25 . The method of  claim 23  wherein said composition that disrupts kinase activity mediated by an EGFR species comprises an active agent that is a nucleic acid molecule that encodes a protein or peptide which interacts with a molecule of an EGFR species to prevent said molecule or from forming a kinase-activity elevating multimeric ensemble with a second molecule.