Method for Identification of Sensitivity of a Patient to Telomerase Inhibition Therapy

Abstract

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 monitoring a patient for an adverse event related to telomerase inhibition therapy wherein the method comprises testing a biological sample from the patient for the length or length distribution of telomeres. 
     
     
         2 . The method of  claim 1 , further comprising the step of identifying the likelihood that a mammalian subject will exhibit an adverse reaction to treatment with a telomerase inhibition therapy. 
     
     
         3 . A method for identifying the likelihood that a mammalian subject will exhibit an adverse reaction to telomerase inhibition therapy comprising,
 (a) determining the average or median telomere length in a biological sample comprising cells obtained from the mammalian subject prior to or at the time of treatment with a telomerase inhibition therapy and multiplying the average or median telomere length by a coefficient to arrive at a telomere length component;   (b) multiplying the intended treatment dosage by a coefficient to arrive at a dosage component; and   (c) producing the sum of the telomere component, the dosage component and a constant; and   (d) determining the expected likelihood of an adverse reaction in the mammalian subject from treatment with the telomerase inhibition therapy.   
     
     
         4 . The method of  claim 1 , wherein the mammalian subject is a human 
     
     
         5 . The method of  claim 2 , wherein the negative reaction is selected from thrombocytopenia, anemia, leucopenia, or neutropenia. 
     
     
         6 . The method of  claim 3 , wherein the adverse reaction is thrombocytopenia, neutropenia or leucopenia. 
     
     
         7 . The method of  claim 3 , wherein the adverse reaction is thrombocytopenia and the sum of the telomere component, the dosage component and the constant determines the percentage decrease of the mammalian subject's platelet number from the subjects platelet number prior to treatment 
     
     
         8 . The method of  claim 7 , wherein the adverse reaction is any grade of thrombocytopenia. 
     
     
         9 . The method of  claim 7 , wherein the adverse reaction is grades 3 or 4 thrombocytopenia. 
     
     
         10 . The method of  claim 1 , wherein the biological sample is blood cells obtained from the mammalian subject. 
     
     
         11 . The method of  claim 10 , wherein the blood cells are white blood cells. 
     
     
         12 . The method of  claim 11 , wherein the white blood cells are granulocytes. 
     
     
         13 . The method of  claim 12 , wherein the blood cells are neutrophils, basophils or eosinophils. 
     
     
         14 . The method of  claim 10 , wherein the blood cells are lymphocytes, monocytes or macrophages. 
     
     
         15 . The method of  claim 14 , wherein the blood cells are lymphocytes. 
     
     
         16 . The method of  claim 1 , wherein the mammalian subject is being treated with the telomerase inhibitor to treat cancer. 
     
     
         17 . The method of  claim 1 , wherein the telomerase inhibitor is an oligonucleotide. 
     
     
         18 . The method of  claim 1 , wherein the telomerase inhibitor is GRN163L. 
     
     
         19 . 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. 
     
     
         20 . The method of  claim 7 , wherein the telomere length component is a positive component when calculating the percentage change. 
     
     
         21 . The method of  claim 7 , wherein the dosage component is a negative component when calculating the percentage change. 
     
     
         22 . The method of  claim 3 , wherein the method further comprises the step of assigning to the subject the likelihood of having an adverse reaction to a telomerase inhibitor therapy. 
     
     
         23 . The method of  claim 3 , wherein, the shorter baseline telomere lengths are associated with an increased risk of an adverse reaction. 
     
     
         24 . The method of  claim 3 , wherein, the increased dosage is associated with an increased risk of an adverse reaction. 
     
     
         25 . The method of  claim 3 , wherein, the baseline telomere length is determined by FISH analysis, 
     
     
         26 . A method of determining the likelihood that a mammalian subject will experience thrombocytopenia related to telomerase inhibition therapy wherein the method comprises,
 (a) determining the average or median telomere length in a biological sample comprising cells obtained from the mammalian subject prior to or at the time of treatment with a telomerase inhibition therapy and multiplying the average or median telomere length by a coefficient to arrive at a telomere length component;   (b) multiplying the intended treatment dosage by a coefficient to arrive at a dosage component;   (c) calculating the sum of the telomere component, the dosage component and the log of the subject's baseline platelet number to determine the predicted platelet nadir during the first weeks of therapy; and   (d) determining the expected likelihood of an adverse reaction in the mammalian subject from treatment with the telomerase inhibition therapy   
     
     
         27 . A method to identify a patient potentially requiring a telomerase inhibitor dose level below the maximum recommended dose level, in which the method comprises
 (a) determining the average or median telomere length in a biological sample comprising cells obtained from the mammalian subject prior to or at the time of treatment with a telomerase inhibition therapy and multiplying the average or median telomere length by a coefficient to arrive at a telomere length component;   (b) multiplying the intended treatment dosage by a coefficient to arrive at a dosage component; and   (c) calculating the sum of the telomere component, the dosage component and the log of the subject's baseline platelet number to determine the predicted platelet nadir during the first weeks of treatment; and   (d) determining the expected likelihood of thrombocytopenia in the mammalian subject from treatment with the telomerase inhibition therapy   (e) administering a reduced dose of the telomerase inhibitor or an reduced dosage regimen of the telomerase inhibitor.   
     
     
         28 . A method to identify a patient requiring an ameliorating pharmaceutical administered in conjunction with a telomerase inhibitor in which the method comprises
 (a) determining the average or median telomere length in a biological sample comprising cells obtained from the mammalian subject prior to or at the time of treatment with a telomerase inhibition therapy and multiplying the average or median telomere length by a coefficient to arrive at a telomere length component;   (b) multiplying the intended treatment dosage by a coefficient to arrive at a dosage component; and   (c) calculating the sum of the telomere component, the dosage component and the log of the subject's baseline platelet number to determine the predicted platelet nadir during the first weeks of treatment; and   (d) determining the expected likelihood of an adverse reaction in the mammalian subject from treatment with the telomerase inhibition therapy   (e) administering an appropriate dosage of an ameliorating pharmaceutical in conjunction with the telomerase inhibitor.   
     
     
         29 . A method for identifying a patient on telomerase inhibition therapy that requires adverse event monitoring comprising testing a biological sample from the patient for telomere length prior to telomerase inhibition therapy. 
     
     
         30 . The method of  claim 27 , further comprising the step of monitoring the patient for an adverse reaction relating to treatment with the telomerase inhibitor. 
     
     
         31 . A computer-accessible medium comprising a database that includes a plurality of records, wherein each record associates (a) information that identifies a subject, with (b) information that indicates whether the subject has shortened telomeres and wherein each record further associates (a) with (c) information that identifies the presence or absence of an adverse event in the subject resulting from administration of a telomerase inhibitor to the subject. 
     
     
         32 . A method for administration of GRN163L which comprises administration of at least about 1.6 mg/kg to about 20 mg/kg of GRN163L on day 1 and on approximately day 8 of a 21 day cycle. 
     
     
         33 . A method for administration of GRN163L which comprises administration of at least about 1.6 mg.kg to about 20 mg/kg of GRN163L on day 1 and on approximately day 15 of a 28 day cycle.