Methods to Treat Cancer with 10-propargyl-10-deazaaminopterin and Methods for Assessing Cancer for Increased Sensitivity to 10-propargyl-10-deazaaminopterin

Abstract

The present invention relates to a method for assessing the sensitivity of a patient's cancer to treatment with 10-propargyl-10-deazaaminopterin and a method for selecting a patient for treatment of cancer with 10-propargyl-10-deazaaminopterin, by determining the amount of a selected polypeptide expressed by the cancer and comparing the amount with the amount of the selected polypeptide expressed by a reference cancer, wherein the polypeptide includes a member of folate pathways within cells and may include at least one of reduced folate carrier-1 enzyme (RFC-1), dihydrofolate reductase (DHFR), folylpoly-gamma-glutamate synthetase (FPGS), thymidylate synthase (TS), γ-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT). The present invention also relates to the use of 10-propargyl-10-deazaaminopterin in the treatment of multiple myeloma.

1 . A method of selecting a patient for treatment of a cancer with 10-propargyl-10-deazaaminopterin, the method comprising the steps of:
 (a) obtaining a sample of the patient's cancer tissue;   (b) determining the expression level of at least one selected polypeptide expressed by the sample;   (c) obtaining a reference expression level for the at least one selected polypeptide for a cancer having sensitivity to 10-propargyl-10-deazaaminopterin;   (d) comparing the expression data for the at least one selected polypeptide of step (b) with the reference expression for the at least one selected polypeptide of step (c), wherein a match of the sample expression of the at least one selected polypeptide to the reference expression of the at least one selected polypeptide indicates the patient's cancer has greater sensitivity to 10-propargyl-10-deazaaminopterin, wherein the at least one selected polypeptide is selected from the group consisting of reduced folate carrier-1 enzyme (RFC-1), dihydrofolate reductase (DHFR), folylpoly-gamma-glutamate synthetase (FPGS), thymidylate synthase (TS), γ-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT); and   (e) selecting the patient for treatment 10-propargyl-10-deazaaminopterin when the expression of the at least one sample polypeptide and the at least one reference polypeptide matches.   
     
     
         2 . The method of  claim 1 , wherein the reference cancer is a T-cell lymphoma, a NSCLC, or a multiple myeloma. 
     
     
         3 . The method of  claim 1 , wherein the at least one selected polypeptide is RFC-1. 
     
     
         4 . The method of  claim 1 , wherein the at least one selected polypeptide is TS. 
     
     
         5 . The method of  claim 1 , wherein the at least one selected polypeptide is DHFR. 
     
     
         6 . The method of  claim 1 , wherein a match is defined as the at least one selected polypeptide having an expression level of at least 50% of the reference's at least one selected polypeptide expression level. 
     
     
         7 . The method of  claim 1 , wherein the patient's cancer is lymphoma, multiple myeloma, or NSCLC. 
     
     
         8 . The method of  claim 7 , wherein the lymphoma is a T-cell lymphoma selected from the group consisting of lymphoblastic lymphomas in which the malignancy occurs in primitive lymphoid progenitors from the thymus; mature or peripheral T-cell neoplasms, including T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, cutaneous T-cell lymphoma (Mycosis fungoides/Sezary syndrome), anaplastic large cell lymphoma, T-cell type, enteropathy-type T-cell lymphoma, Adult T-cell leukemia/lymphoma including those associated with HTLV-1, and angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitic T-cell lymphoma; and peripheral T-cell lymphomas that initially involve a lymph node paracortex. 
     
     
         9 . A method for assessing sensitivity of a patient's cancer to treatment with 10-propargyl-10-deazaaminopterin comprising the steps of:
 (a) obtaining a sample of the patient's cancer tissue;   (b) determining the expression level of at least one selected polypeptide expressed by the sample;   (c) obtaining a reference expression level for the at least one selected polypeptide for a least one cancer having sensitivity to 10-propargyl-10-deazaaminopterin;   (d) comparing the expression data for the at least one selected polypeptide of step (b) with the reference expression for the at least one selected polypeptide of step (c), wherein a match of the sample expression level of the at least one selected polypeptide to the reference expression level of the at least one selected polypeptide indicates the patient's cancer has greater sensitivity to 10-propargyl-10-deazaaminopterin, wherein the at least one selected polypeptide is selected from the group consisting of reduced folate carrier-1 enzyme (RFC-1), dihydrofolate reductase (DHFR), folylpoly-gamma-glutamate synthetase (FPGS), thymidylate synthase (TS), γ-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT); and   (e) generating a report of the sensitivity of the sample to 10-propargyl-10-deazaaminopterin.   
     
     
         10 . The method of  claim 9 , wherein the reference cancer is a T-cell lymphoma, NSCLC, or multiple myeloma. 
     
     
         11 . The method of  claim 9 , wherein the at least one selected polypeptide is RFC-1. 
     
     
         12 . The method of  claim 9 , wherein the at least one selected polypeptide is TS. 
     
     
         13 . The method of  claim 9 , wherein the at least one selected polypeptide is DHFR. 
     
     
         14 . The method of  claim 9 , wherein a match is defined as the at least one selected polypeptide having an expression level of at least 50% of the reference's at least one selected polypeptide expression level. 
     
     
         15 . The method of  claim 9 , wherein the patient's cancer is lymphoma, NSCLC, or multiple myeloma. 
     
     
         16 . The method of  claim 15 , wherein the lymphoma is a T-cell lymphoma selected from the group consisting of lymphoblastic lymphomas in which the malignancy occurs in primitive lymphoid progenitors from the thymus; mature or peripheral T-cell neoplasms, including T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, cutaneous T-cell lymphoma (Mycosis fungoides/Sezary syndrome), anaplastic large cell lymphoma, T-cell type, enteropathy-type T-cell lymphoma, Adult T-cell leukemia/lymphoma including those associated with HTLV-1, and angioimmunoblastic T-cell lymphoma, and subcutaneous panniculitic T-cell lymphoma; and peripheral T-cell lymphomas that initially involve a lymph node paracortex. 
     
     
         17 . A method for the treatment of multiple myeloma comprising administering to a patient diagnosed with having multiple myeloma a pharmaceutically acceptable composition comprising a therapeutically effective amount of 10-propargyl-10-deazaaminopterin. 
     
     
         18 . The method of  claim 17 , wherein the 10-propargyl-10-deazaaminopterin is substantially free of 10-deazaaminopterin. 
     
     
         19 . The method of  claim 17 , wherein the 10-propargyl-10-deazaaminopterin is administered in an amount of from about 30 to about 275 mg/m 2  per dose. 
     
     
         20 . A method to modulate the expression of a polypeptide in a patient's cancer comprising administering to the patient an effective amount of 10-propargyl-10-deazaaminopterin, wherein the polypeptide is selected from the group consisting of reduced folate carrier-1 enzyme (RFC-1), dihydrofolate reductase (DHFR), folylpoly-gamma-glutamate synthetase (FPGS), thymidylate synthase (TS), γ-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT). 
     
     
         21 . The method of  claim 20 , wherein the patient has lymphoma, multiple myeloma, or NSCLC. 
     
     
         22 . The method of  claim 20 , wherein the modulation is down-regulation and the polypeptide is TS or DHFR. 
     
     
         23 . The method of  claim 20 , wherein the 10-propargyl-10-deazaaminopterin is substantially free of 10-deazaaminopterin. 
     
     
         24 . The method of  claim 20 , wherein the 10-propargyl-10-deazaaminopterin is administered in an amount of from about 30 to about 275 mg/m 2  per dose. 
     
     
         25 . The method of  claim 20 , wherein the polypeptide is RFC-1. 
     
     
         26 . A kit for assessing sensitivity of a patient's cancer to treatment with 10-propargyl-10-deazaaminopterin comprising at least two sets of selected polypeptide RNA-specific primers wherein each set of specific primers produces double stranded DNA complementary to at least one selected polypeptides, wherein each first primers of said sets contains a sequence which can selectively hybridize to RNA, cDNA or an EST complementary to one of the selected polypeptides to create an extension product and each said second primers of said sets is capable of selectively hybridizing to said extension product, wherein the at least one selected polypeptide is selected from the group consisting of reduced folate carrier-1 enzyme (RFC-1), dihydrofolate reductase (DHFR), folylpoly-gamma-glutamate synthetase (FPGS), thymidylate synthase (TS), γ-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT). 
     
     
         27 . The kit of  claim 26 , wherein the at least one selected peptide is RFC-1.