Treatment of carcinomas with a combination of EGF-pathway and telomerase inhibitors
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.
1. A method for inhibiting the proliferation of carcinoma cells that express an EGF receptor, comprising
(a) exposing the cells to an anti-EGF receptor antibody trastuzumab, and
(b) either preceding, following, or concomitantly with step (a), exposing the cells to a telomerase inhibitor comprising an oligonucleotide which is characterized by:
(i) N3′→P5′ thiophosphoramidate internucleoside linkages;
(ii) comprising 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
wherein the carcinoma cells are breast cancer or non-small cell lung cancer cells.
2. The method of claim 1 , wherein the oligonucleotide is 13-20 bases in length.
3. The method of claim 2 wherein the telomerase inhibitor is the compound designated herein as GRN163L.
4. 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 the carcinoma cells in the subject.
5. The method of claim 4 , for use in treating a subject having breast cancer characterized by overexpression of HER2 in the carcinoma cells, wherein the 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 the carcinoma cells in the subject.
6. The method of claim 4 , 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.
7. The method of claim 4 , 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 μM.
8. A method for enhancing the treatment efficacy of an anti-EGF receptor antibody trastuzumab in a subject with a carcinoma that express an EGF receptor, comprising
administering to the subject, before, during, or after administering the anti-EGF receptor antibody trastuzumab, an oligonucleotide telomerase inhibitor 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
wherein the carcinoma is breast cancer or non-small cell lung cancer.
9. The method of claim 8 , wherein the telomerase inhibitor is administered in an amount effective to inhibit the proliferation of carcinoma cells in the subject, when the telomerase inhibitor is administered alone.
10. The method of claim 8 , 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.
11. The method of claim 8 , wherein the oligonucleotide telomerase inhibitor is GRN163L.
12. The method of claim 11 , 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.