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Last Updated: March 28, 2024

Details for Patent: 8,168,404


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Title: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-deazaminopterin and a method for selecting a patient for treatment of cancer with 10-propargyl-10-deazaminopterin, 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), .gamma.-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT). The present invention also relates to the use of 10-propargyl-10-deazaminopterin in the treatment of multiple myeloma.
Inventor(s): O'Connor; Owen A. (Scarsdale, NY), Sirotnak; Francis M. (Hampton Bays, NY)
Assignee: Sloan-Kettering Institute for Cancer Research (New York, NY)
Filing Date:Dec 14, 2009
Application Number:12/637,254
Claims: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 in the sample; (c) comparing the determined expression level in the sample with a reference expression level for the same at least one polypeptide; and (d) selecting the patient for treatment 10-propargyl-10-deazaaminopterin where the comparison of the expression level in the sample of the at least one polypeptide and the corresponding reference expression levels indicate 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), .gamma.-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT).

2. The method of claim 1, wherein the at least one selected polypeptide is RFC-1.

3. The method of claim 1, wherein the at least one selected polypeptide is FPGS.

4. The method of claim 1, wherein the at least one selected polypeptide is DHFR.

5. The method of claim 1, wherein the patient's cancer is lymphoma, multiple myeloma, or NSCLC.

6. The method of claim 5, 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.

7. 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 in the sample; (c) comparing the determined expression level in the sample with a reference expression level for the same at least one polypeptide to determine whether the reference expression level for a polypeptide is indicative for the expression level of that polypeptide in samples that are sensitive to 10-propargyl-10-deazaaminopterin; and (d) generating a report of the sensitivity of the sample 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), .gamma.-glutamyl hydrolase (GGH), and glycinamide ribonucleotide formyltransferase (GARFT).

8. The method of claim 1, wherein the cancer is a T-cell lymphoma, NSCLC, or multiple myeloma.

9. The method of claim 7, wherein the at least one selected polypeptide is RFC-1.

10. The method of claim 7, wherein the at least one selected polypeptide is FPGS.

11. The method of claim 7, wherein the at least one selected polypeptide is DHFR.

12. The method of claim 7, wherein the patient's cancer is lymphoma, NSCLC, or multiple myeloma.

13. The method of claim 12, 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.

14. A method for assessing sensitivity of a lymphoma to treatment with 10-propargyl-10-deazaaminopterin comprising the steps of (a) obtaining a sample of the lymphoma; (b) determining the amount of reduced folate carrier-1 enzyme (RFC-1) expressed by the sample, wherein higher levels of expressed RFC-1 are indicative of sensitivity to 10-propargyl-10-deazaaminopterin; and (c) generating a report of the sensitivity of the sample to 10-propargyl-10-deazaaminopterin.

15. The method of claim 1, wherein the at least one selected polypeptide is TS.

16. The method of claim 1, wherein the at least one selected polypeptide is GGH.

17. The method of claim 1, wherein the at least one selected polypeptide is GARFT.

18. The method of claim 7, wherein the at least one selected polypeptide is TS.

19. The method of claim 7, wherein the at least one selected polypeptide is GGH.

20. The method of claim 7, wherein the at least one selected polypeptide is GARFT.

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