Treatment of Carcinomas with a Combination of EGF-Pathway and Telomerase Inhibitors

Abstract

A method and kit for inhibiting the proliferation of carcinoma cells are disclosed, based on a combination of an EGF pathway inhibitor and a telomerase inhibitor. When used in cancer therapy, the two compounds in combination enhance the anti-cancer treatment efficacy obtained with the antibody alone or the telomerase inhibitor alone.

It is claimed: 
     
         1 . A method for inhibiting the proliferation of carcinoma cells, comprising
 (a) exposing the cells to an anti-EGF receptor antibody, and   (b) either proceeding, following, or concomitantly with step (a), exposing the cells to a telomerase inhibitor.   
     
     
         2 . The method of  claim 1 , wherein the telomerase inhibitor includes an oligonucleotide having nuclease-resistant intersubunit linkages and an oligonucleotide sequence effective to bind by sequence-specific hybridization to a template region of hTR. 
     
     
         3 . The method of  claim 2 , wherein the internucleoside linkages in the oligonucleotide are selected from N3′→P5′ phosphoramidate and N3′3→P5′ thiophosphoramidate linkages. 
     
     
         4 . The method of  claim 2 , wherein the telomerase inhibitor includes a lipid moiety (i) selected from the group consisting of fatty acids, sterols, and derivatives thereof, and (ii) attached covalently to one end of the oligonucleotide. 
     
     
         5 . The method of  claim 2 , wherein the oligonucleotide is 10-20 bases in length. 
     
     
         6 . The method of  claim 5 , wherein the oligonucleotide is characterized by:
 (i) N3′→P5′ thiophosphoramidate internucleoside linkages;   (ii) having the sequence identified as SEQ ID NO: 12; and   (iii) a palmitoyl (C16) moiety linked to the 5′ terminus of the oligonucleotide via a glycerol or aminoglycerol linker.   
     
     
         7 . The method of  claim 6 , wherein the telomerase inhibitor is the compound designated herein as GRN163L. 
     
     
         8 . The method of  claim 1 , for use in treating a subject having carcinoma, wherein exposing step (a) includes administering the anti-EGF receptor antibody to the subject in an amount effective, when the antibody is administered alone, to inhibit proliferation of cancer cells in the subject. 
     
     
         9 . The method of  claim 8 , for use in treating a subject having breast or ovarian cancer characterized by overexpression of HER2 in the cancer cells, wherein the anti-EGF receptor antibody is an anti-HER2 antibody, and exposing step (a) includes administering the anti-HER2 antibody to the subject in an amount effective, when the antibody is administered alone, to inhibit proliferation of cancer cells in the subject. 
     
     
         10 . The method of  claim 8 , wherein each exposing step (a) and (b) includes administering the respective antibody and inhibitor to the subject in an amount effective, when each compound is administered alone, to inhibit proliferation of cancer cells in the subject. 
     
     
         11 . The method of  claim 8 , wherein the telomerase inhibitor is the compound GRN163L, and step (b) includes infusing the telomerase inhibitor intravenously into the subject, under infusion conditions effective to produce a blood concentration of the telomerase inhibitor of between 1 nM and 100 uM. 
     
     
         12 . A method for enhancing the treatment efficacy of an anti-EGF receptor antibody in a subject with a carcinoma, comprising
 administering to the subject, before, during, or after administering the anti-EGF receptor antibody, an oligonucleotide telomerase inhibitor of the type composed of an oligonucleotide having nuclease-resistant intersubunit linkages and an oligonucleotide sequence effective to bind by sequence-specific hybridization to a template region of hTR.   
     
     
         13 . The method of  claim 12 , wherein the telomerase inhibitor is administered in an amount effective to inhibit the proliferation of cancer cells in the subject, when the telomerase inhibitor is administered alone. 
     
     
         14 . The method of  claim 12 , wherein enhanced treatment efficacy is evidenced by an increased survival time of the subject, inhibition of tumor growth in the subject, or a combination thereof. 
     
     
         15 . The method of  claim 12 , wherein the oligonucleotide telomerase inhibitor is characterized by:
 (i) N3′→P5′ thiophosphoramidate internucleoside linkages;   (ii) having the sequence identified as SEQ ID NO: 12; and   (iii) a palmitoyl (C16) moiety linked to the 5′ terminus of the oligonucleotide via a glycerol or aminoglycerol linker.   
     
     
         16 . The method of  claim 15 , wherein the oligonucleotide telomerase inhibitor is GRN163L. 
     
     
         17 . The method of  claim 16 , wherein said administering includes infusing the oligonucleotide telomerase inhibitor intravenously into the subject, under infusion conditions effective to produce a blood concentration of the inhibitor of between 1 nM and 100 μM. 
     
     
         18 . The method of  claim 12 , wherein the anti-EGF receptor antibody is an anti-HER2 antibody. 
     
     
         19 . A kit for use in treating a carcinoma in a subject, comprising
 (a) a dose of an anti-EGF receptor antibody, in an amount of the antibody effective, when administered alone, to inhibit the proliferation of carcinoma cells in the subject, and   (b) a dose of an oligonucleotide telomerase inhibitor having nuclease-resistant intersubunit linkages and an oligonucleotide sequence effective to bind by sequence-specific hybridization to a template region of hTR.   
     
     
         20 . The kit of  claim 19 , wherein the oligonucleotide is characterized by:
 (i) N3′→P5′ thiophosphoramidate internucleoside linkages;   (ii) having the sequence identified as SEQ ID NO: 12; and   (iii) a palmitoyl (C16) moiety linked to the 5′ terminus of the oligonucleotide via a glycerol or aminoglycerol linker.   
     
     
         21 . The kit of  claim 20 , wherein the telomerase inhibitor is the compound designated herein as GRN163L. 
     
     
         22 . The kit of  claim 21 , wherein the anti-EGF receptor antibody is an anti-HER2 antibody. 
     
     
         23 . The use of an anti-EGF receptor antibody and a telomerase inhibitor in the manufacture of a medicament for treating a carcinoma in a subject. 
     
     
         24 . The use of a telomerase inhibitor in the manufacture of a medicament for treating a carcinoma in a subject who is being treated with an anti-EGF receptor antibody, for the purpose of enhancing the anti-cancer efficacy of the antibody in the subject.