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: 
     
         1 - 47 . (canceled) 
     
     
         48 . A method of treating an individual with a solid tumor, which method comprises the steps of:
 (a) administering to said individual an anti-EGFR antibody which inhibits formation of erbB receptor protein dimers that produce elevated tyrosine kinase activity in cells of said tumor, said inhibition having a cytostatic effect on cells of said tumor such that the tumor cells accumulate in the G1 phase of the cell cycle; and   (b) thereafter exposing said individual to a therapeutically effective amount of external beam anti-cancer radiation selected from the group consisting of gamma rays and x-rays,   wherein said treatment causes an increase in apoptosis of the cells in said tumor as compared to a tumor that has not been pre-treated with said antibody, and wherein said treatment causes a decrease in clonogenic survival of the cells in said tumor as compared to a tumor that has not been pre-treated with said antibody.   
     
     
         49 . A method of treating an individual with a solid tumor, which method comprises the steps of:
 (a) administering to said individual an anti-EGFR antibody which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in a tumor cell, said inhibition having a cytostatic effect on the tumor cell; and   (b) thereafter exposing said individual to a therapeutically effective amount of external beam anti-cancer radiation selected from the group consisting of gamma rays and x-rays.   
     
     
         50 . The method of  claim 49 , wherein said anti-cancer radiation is x-rays. 
     
     
         51 . The method of  claim 49 , wherein said antibody causes accumulation of tumor cells in the G1 phase of the cell cycle. 
     
     
         52 . The method of  claim 49 , wherein said treatment causes an increase in apoptosis of cells in said tumor as compared to a tumor that has not been pre-treated with said antibody. 
     
     
         53 . The method of  claim 49 , wherein said treatment causes a decrease in clonogenic survival of cells in said tumor as compared to a tumor that has not been pre-treated with said antibody. 
     
     
         54 . A method of enhancing apoptosis of tumor cells in a patient comprising:
 (a) Administering an anti-EGFR antibody to the patient, wherein the antibody inhibits signaling via an ErbB receptor on the tumor cell and thereby arrests the cell cycle of the tumor cell in G1 phase, and thereafter   (b) Administering a cytotoxic therapy to the patient, wherein said cytotoxic therapy is selected from the group consisting of chemotherapy, x-ray radiation therapy and external beam gamma radiation therapy,   wherein said tumor cells are in a solid tumor, and   wherein apoptosis of said tumor is increased as compared to a tumor that has not been pre-treated with said antibody.   
     
     
         55 . A method of decreasing clonogenic survival of tumor cells in a patient comprising:
 (a) Administering an anti-EGFR antibody to the patient, wherein the antibody inhibits signaling via an ErbB receptor on the tumor cells and thereby arrests the cell cycle of the tumor cells in G1 phase, and thereafter   (b) Administering a cytotoxic therapy to the patient, wherein said cytotoxic therapy is selected from the group consisting of chemotherapy, x-ray radiation therapy and external beam gamma radiation therapy, wherein   said tumor cells are in a solid tumor, and wherein clonogenic survival of said tumor is decreased as compared to a tumor that has not been pre-treated with said antibody.   
     
     
         56 . The method of  claim 54 , wherein said anti-EGFR antibody inhibits formation of erbB receptor protein dimers that produce elevated tyrosine kinase activity in cells of said tumor. 
     
     
         57 . The method of  claim 54 , wherein said cytotoxic therapy is chemotherapy. 
     
     
         58 . The method of  claim 54 , wherein said cytotoxic therapy is x-ray radiation therapy. 
     
     
         59 . The method of  claim 54 , wherein said cytotoxic therapy is gamma radiation therapy 
     
     
         60 . The method of  claim 54 , wherein said tumor is a colorectal tumor. 
     
     
         61 . The method of  claim 54 , wherein said tumor is refractory to said cytotoxic therapy. 
     
     
         62 . The method of  claim 57 , wherein said tumor is refractory to said cytotoxic therapy. 
     
     
         63 . The method of  claim 60 , wherein said tumor is refractory to said cytotoxic therapy. 
     
     
         64 . A method for rendering a refractory, EGFR-expressing tumor cell in a patient diagnosed with cancer sensitive to a cytotoxic therapy, comprising:
 (a) first administering to said patient an anti-EGFR antibody in the absence of a cytotoxic therapy, and   (b) after a sufficient time such that the antibody binds to said tumor cell and inhibits EGFR-associated tyrosine kinase activity, administering a therapeutically effective amount of said cytotoxic therapy,   wherein the antibody has a cytostatic effect on the tumor cell,   wherein said tumor cell is a solid tumor cell, and   wherein said cytotoxic therapy is selected from the group consisting of chemotherapy, x-ray radiation therapy and external beam gamma radiation therapy.   
     
     
         65 . A method for treating a cancer patient with a recurrent cancer, comprising:
 (a) first administering to said patient an anti-EGFR antibody, and   (b) after a sufficient time such that the antibody binds to said tumor cell and inhibits EGFR-associated tyrosine kinase activity, administering a therapeutically effective amount of said cytotoxic therapy,   wherein the antibody has a cytostatic effect on the tumor cell,   wherein said tumor cell is a solid tumor cell, and   wherein said cytotoxic therapy is selected from the group consisting of chemotherapy, x-ray radiation therapy and external beam gamma radiation therapy.   
     
     
         66 . The method of  claim 64 , wherein said cytotoxic therapy is chemotherapy. 
     
     
         66 . The method of  claim 64 , wherein said cytotoxic therapy is x-ray radiation therapy. 
     
     
         67 . The method of  claim 64 , wherein said cytotoxic therapy is gamma ray radiation therapy. 
     
     
         68 . The method of  claim 64 , wherein cells of said tumor exhibit an increased rate of apoptosis following treatment with said cytotoxic therapy as compared to cytotoxic therapy treatment in the absence of prior administration of said antibody. 
     
     
         69 . The method of  claim 64 , wherein said refractory tumor cell has exhibited resistance to cytotoxic treatment. 
     
     
         70 . The method of  claim 64 , wherein said patient has relapsed or is at risk of relapsing following a prior cytotoxic treatment. 
     
     
         71 . The method of  claim 64 , wherein said anti-EGFR antibody arrests said tumor cell in the G1 phase of the cell cycle. 
     
     
         72 . The method of  claim 48 , wherein the cytotoxic therapy is administered beginning within 1 to 10 hours after administration of the anti-EGFR antibody. 
     
     
         73 . The method of any one of  claim 48 , wherein the cytotoxic therapy is administered beginning within 3 hours after administration of the anti-EGFR antibody. 
     
     
         74 . The method of any one of  claim 48 , wherein the cytotoxic therapy is administered beginning within 24 hours after administration of the anti-EGFR antibody. 
     
     
         75 . The method of any one of  claim 48 , wherein the cytotoxic therapy is administered beginning within 72 hours after administration of the anti-EGFR antibody. 
     
     
         76 . The method of any one of  claim 48 , wherein the cytotoxic therapy is administered as multiple doses over several days, hours or weeks following said antibody administration. 
     
     
         77 . The method of any one of  claim 48 , wherein said antibody is administered intravenously. 
     
     
         78 . The method of any one of  claim 48 , wherein said solid tumor is an epithelial solid tumor. 
     
     
         79 . The method of any one of  claim 48 , wherein said solid tumor is a colorectal tumor. 
     
     
         80 . The method of any one of  claim 48 , wherein the antibody inhibits formation of an EGFR homodimer. 
     
     
         81 . The method of any one of  claim 48 , wherein the antibody inhibits formation of a heterodimer of p185 and EGFR. 
     
     
         82 . A method of treating an individual with a solid tumor, which method comprises the steps of:
 (a) administering to said individual an anti-EGFR antibody which inhibits formation of erbB protein dimers that produce elevated tyrosine kinase activity in cells of said tumor, said inhibition having a cytostatic effect on the tumor cell; and   (b) thereafter administering to said individual a therapeutically effective amount of chemotherapy.   
     
     
         83 . The method of  claim 82 , wherein said antibody causes accumulation of tumor cells in the G1 phase of the cell cycle. 
     
     
         84 . The method of  claim 82 , wherein said treatment causes an increase in apoptosis of cells in said tumor as compared to a tumor that has not been pre-treated with said antibody. 
     
     
         85 . The method of  claim 82 , wherein said treatment causes a decrease in clonogenic survival of cells in said tumor as compared to a tumor that has not been pre-treated with said antibody. 
     
     
         86 . The method of  claim 82 , wherein the cytotoxic therapy is administered beginning within 1 to 10 hours after administration of the anti-EGFR antibody. 
     
     
         87 . The method of  claim 82 , wherein the cytotoxic therapy is administered beginning within 3 hours after administration of the anti-EGFR antibody. 
     
     
         88 . The method of  claim 82 , wherein the cytotoxic therapy is administered beginning within 24 hours after administration of the anti-EGFR antibody. 
     
     
         89 . The method of  claim 82 , wherein the cytotoxic therapy is administered beginning within 72 hours after administration of the anti-EGFR antibody. 
     
     
         90 . The method of  claim 82 , wherein the cytotoxic therapy is administered as multiple doses over several days, hours or weeks following said antibody administration. 
     
     
         91 . The method of  claim 82 , wherein said antibody is administered intravenously. 
     
     
         92 . The method of  claim 82 , wherein said solid tumor is an epithelial solid tumor. 
     
     
         93 . The method of  claim 82 , wherein said solid tumor is a colorectal tumor. 
     
     
         94 . The method of  claim 82 , wherein the antibody inhibits formation of an EGFR homodimer. 
     
     
         95 . The method of  claim 82 , wherein the antibody inhibits formation of a heterodimer of p185 and EGFR.