Method for identification of sensitivity of a patient to telomerase inhibition therapy
The invention provides methods for determining the susceptibility of cancer patients to developing adverse reactions if treated with a telomerase inhibitor drug by measurement of telomere length in appropriate cells of the patient prior to initiation of the telomerase inhibitor treatment.
1. A method of treating a human subject on telomerase inhibition therapy, the method comprising:
assaying average or median telomere length of a non-cancerous biological cellular sample obtained from a human subject undergoing therapy with a telomerase inhibitor to detect a change from a baseline telomere length; and
administering a reduced therapeutic dose or a reduced dosage regimen of the telomerase inhibitor to the human subject who exhibits a reduction in average or medial telomere length in the non-cancerous biological cellular sample obtained from the human subject relative to the baseline telomere length;
wherein the administering inhibits telomerase and the proliferation of cancer cells in the human subject with a reduced risk of an adverse reaction.
2. The method of claim 1 , wherein the adverse reaction is selected from at least one of thrombocytopenia, anemia, leucopenia and neutropenia.
3. The method of claim 1 , wherein the adverse reaction is thrombocytopenia.
4. The method of claim 1 , wherein the assaying comprises assaying a percentage decrease in the human subject's platelet number from the human subject's platelet number prior to telomerase inhibition therapy.
5. The method of claim 3 , wherein the assaying comprises
(a) multiplying the average or median telomere length by a coefficient to arrive at a telomere length component;
(b) multiplying an intended treatment dosage by a coefficient to arrive at a dosage component;
(c) calculating the sum of the telomere component and the dosage component and the log of the subject's baseline platelet number to determine a predicted platelet nadir during treatment; and
(d) determining the expected likelihood of thrombocytopenia in the human subject from treatment with the telomerase inhibition therapy.
6. The method of claim 1 , wherein the baseline telomere length is the average or median length of the human subject's telomeres in a non-cancerous biological cellular sample prior to the first treatment of the telomerase inhibitor.
7. The method of claim 1 , wherein the baseline telomere length is the average or median length of the human subject's telomeres in a non-cancerous biological cellular sample at the same time the human subject receives the first treatment of the telomerase inhibitor.
8. The method of claim 1 , wherein the baseline telomere length is determined by FISH analysis.
9. The method of claim 1 , wherein the non-cancerous biological sample comprises white blood cells.
10. The method of claim 9 , wherein the white blood cells are selected from granulocytes, lymphocytes, monocytes and macrophages.
11. The method of claim 10 , wherein the white blood cells are granulocytes selected from neutrophils, basophils and eosinophils.
12. The method of claim 10 , wherein the white blood cells are selected from lymphocytes, monocytes and macrophages.
13. The method of claim 1 , wherein the telomerase inhibitor is an oligonucleotide.
14. The method of claim 13 , wherein the oligonucleotide is 13-20 bases in length and comprises: a sequence 5′-TAGGGTTAGACAA-3′ (SEQ ID NO:2) wherein the internucleoside linkages are N3′→P5′ thiophosphoramidate internucleoside linkages; and a palmitoyl (C16) moiety linked to the 5′ end of the oligonucleotide through a glycerol or aminoglycerol linker; or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , wherein the telomerase inhibitor is GRN163L.
16. The method of claim 1 , wherein the human subject is being treated for cancer.
17. The method of claim 16 , wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, prostate cancer, testicular cancer, hepatocellular cancer, gastric cancer, gastrointestinal cancer, pharynx cancer, rectal cancer, pancreatic cancer, cervical cancer ovarian cancer, liver cancer, bladder cancer, cancer of the ‘urinary tract, thyroid cancer, renal cancer, skin cancer, brain cancer, carcinoma, melanoma, leukemia and lymphoma.