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1. (WO2014153209) ANTISENSE OLIGONUCLEOTIDES FOR TREATMENT OF CANCER STEM CELLS
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CLAIMS

What is claimed is:

1. A method of suppressing metastasis of a cancer in an individual comprising

administering to the individual an effective amount of one or more oligonucleotide complementary to an antisense non-coding chimeric mitochondrial RNA

(ASncmtRNA) molecule or a sense non-coding chimeric mitochondrial RNA (SncmtRNA) molecule, wherein the oligonucleotide is able to hybridize with the chimeric mitochondrial RNA molecules to form a stable duplex, and wherein the individual has been previously treated for cancer with a therapy.

2. The method of claim 1, wherein the oligonucleotide is sufficiently complementary to a human non-coding chimeric mitochondrial RNA molecule comprising:

a. an antisense 16S mitochondrial ribosomal RNA covalently linked at its 5' end to the 3' end of a polynucleotide with an inverted repeat sequence or b. a sense 16S mitochondrial ribosomal RNA covalently linked at its 5' end to the 3' end of a polynucleotide with an inverted repeat sequence.

3. The method of claim 1 or 2, wherein the oligonucleotide is complementary to the ASncmtRNA molecule encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

4. The method of claim 1 or 2, wherein the oligonucleotide is at least 85%

complementary to the ASncmtRNA molecule encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

5. The method of any one of claims 1-4, wherein the one or more oligonucleotide

comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs:7-198.

6. The method of any one of claims 1-5, wherein the oligonucleotide is administered in combination with at least one anti-cancer agent.

7. The method of claim 6, wherein the at least one anti-cancer agent is selected from the group consisting of remicade, docetaxel, celecoxib, melphalan, dexamethasone, steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinib, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bortezomib, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, estrainustine sodium phosphate, sulindac, and etoposide.

8. The method of claim 6, wherein the oligonucleotide and the at least one anti-cancer agent is administered sequentially.

9. The method of claim 6, wherein the oligonucleotide and the at least one anti-cancer agent is administered simultaneously.

10. The method of any one of claims 1-9, wherein the oligonucleotide is administered in combination with a radiation therapy.

11. The method of any one of claims 1-10, wherein the oligonucleotide is administered in combination with surgery.

12. The method of any one of claims 1-11, wherein the oligonucleotide is administered in combination with an allogenic stem cell transplant therapy.

13. The method of any one of claims 1-12, wherein the oligonucleotide is administered in combination with an autologous stem cell transplant therapy.

14. The method of any one of claims 1-13, wherein the individual has been previously treated for cancer with a therapy comprising chemotherapy, radiation therapy, surgery, or combinations thereof.

15. The method of any one of claims 1-14, wherein the cancer in the individual relapsed after treatment with one or more of bortezomib, cyclophosphamide, dexamethasone, doxorubicin, interferon-alpha, lenalidomide, melphalan, pegylated interferon-alpha, prednisone, thalidomide, and vincristine.

16. The method of any one of claims 1-15, wherein the cancer is a solid cancer.

17. The method of claim 16, wherein the solid cancer is bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, liver and bile duct cancer, lung cancer, melanoma, oral cancer, ovarian cancer, pancreatic cancer, pharynx cancer, prostate cancer, renal cancer, testicular cancer, or thyroid cancer.

18. The method of any one of claims 1-15, wherein the cancer is a non-solid cancer.

19. The method of claim 18, wherein the non-solid cancer is multiple myeloma, leukemia, or lymphoma.

20. The method of any one of claims 1-19, wherein the oligonucleotide reduces the

number of cancer stem cells in the individual as compared to an individual not administered the oligonucleotide.

21. The method of any one of claims 1-20, wherein the oligonucleotide inhibits tumor growth and/or metastasis in the individual as compared to an individual not administered the oligonucleotide.

22. A method for treating or preventing relapse of cancer in an individual comprising administering to the individual an effective amount of one or more oligonucleotide complementary to an antisense non-coding chimeric mitochondrial RNA

(ASncmtRNA) molecule or a sense non-coding chimeric mitochondrial RNA

(SncmtRNA) molecule, wherein the oligonucleotide is able to hybridize with the chimeric mitochondrial RNA molecules to form a stable duplex, and wherein the individual has been previously treated for cancer with a therapy.

23. The method of claim 22, wherein the oligonucleotide is sufficiently complementary to a human non-coding chimeric mitochondrial RNA molecule comprising:

a. an antisense 16S mitochondrial ribosomal RNA covalently linked at its 5' end to the 3' end of a polynucleotide with an inverted repeat sequence or b. a sense 16S mitochondrial ribosomal RNA covalently linked at its 5' end to the 3' end of a polynucleotide with an inverted repeat sequence.

24. The method of claim 22 or 23, wherein the oligonucleotide is complementary to the ASncmtRNA molecule encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

25. The method of claim 22 or 23, wherein the oligonucleotide is at least 85%

complementary to the ASncmtRNA molecule encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

26. The method of any one of claims 22-25, wherein the one or more oligonucleotide comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs:7-198.

27. The method of any one of claims 22-26, wherein the oligonucleotide is administered in combination with at least one anti-cancer agent.

28. The method of claim 27, wherein the at least one anti-cancer agent is selected from the group consisting of remicade, docetaxel, celecoxib, melphalan, dexamethasone, steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinib, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bortezomib, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, estrainustine sodium phosphate, sulindac, and etoposide.

29. The method of claim 27, wherein the oligonucleotide and the at least one anti-cancer agent is administered sequentially.

30. The method of claim 27, wherein the oligonucleotide and the at least one anti-cancer agent is administered simultaneously.

31. The method of any one of claims 22-30, wherein the oligonucleotide is administered in combination with a radiation therapy.

32. The method of any one of claims 22-31, wherein the oligonucleotide is administered in combination with surgery.

33. The method of any one of claims 22-32, wherein the oligonucleotide is administered in combination with an allogenic stem cell transplant therapy.

34. The method of any one of claims 22-32, wherein the oligonucleotide is administered in combination with an autologous stem cell transplant therapy.

35. The method of any one of claims 22-34, wherein the individual has been previously treated for cancer with a therapy comprising chemotherapy, radiation therapy, surgery, or combinations thereof.

36. The method of any one of claims 22-35, wherein the cancer in the individual relapsed after treatment with one or more of bortezomib, cyclophosphamide, dexamethasone, doxorubicin, interferon-alpha, lenalidomide, melphalan, pegylated interferon-alpha, prednisone, thalidomide, and vincristine.

37. The method of any one of claims 22-36, wherein the cancer is a solid cancer.

38. The method of claim 37, wherein the solid cancer is bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, liver and bile duct cancer, lung cancer, melanoma, oral cancer, ovarian cancer, pancreatic cancer, pharynx cancer, prostate cancer, renal cancer, testicular cancer, or thyroid cancer.

39. The method of any one of claims 22-36, wherein the cancer is a non-solid cancer.

40. The method of claim 39, wherein the non-solid cancer is multiple myeloma, leukemia, or lymphoma.

41. The method of any one of claims 22-40, wherein the oligonucleotide reduces the

number of cancer stem cells in the individual as compared to an individual not administered the oligonucleotide.

42. The method of any one of claims 22-41, wherein the oligonucleotide inhibits tumor growth and/or metastasis in the individual as compared to an individual not administered the oligonucleotide.

43. A method for the treatment of metastatic cancer in an individual comprising

administering to the individual an effective amount of one or more oligonucleotide complementary to an antisense non-coding chimeric mitochondrial RNA

(ASncmtRNA) molecule or a sense non-coding chimeric mitochondrial RNA

(SncmtRNA) molecule, wherein the oligonucleotide is able to hybridize with the chimeric mitochondrial RNA molecules to form a stable duplex, and wherein the individual has been previously treated for cancer with a therapy.

44. The method of claim 43, wherein the oligonucleotide is sufficiently complementary to a human non-coding chimeric mitochondrial RNA molecule comprising:

a. an antisense 16S mitochondrial ribosomal RNA covalently linked at its 5' end to the 3' end of a polynucleotide with an inverted repeat sequence or b. a sense 16S mitochondrial ribosomal RNA covalently linked at its 5' end to the 3' end of a polynucleotide with an inverted repeat sequence.

45. The method of claim 43 or 44, wherein the oligonucleotide is complementary to the ASncmtRNA molecule encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

46. The method of claim 43 or 44 wherein the oligonucleotide is at least 85%

complementary to the ASncmtRNA molecule encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

47. The method of any one of claims 43-46, wherein the one or more oligonucleotide comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs:7-198.

48. The method of any one of claims 43-47, wherein the oligonucleotide is administered in combination with at least one anti-cancer agent.

49. The method of claim 48, wherein the at least one anti-cancer agent is selected from the group consisting of remicade, docetaxel, celecoxib, melphalan, dexamethasone, steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, gefitinib, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha, capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bortezomib, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, estrainustine sodium phosphate, sulindac, and etoposide.

50. The method of claim 48, wherein the oligonucleotide and the at least one anti-cancer agent is administered sequentially.

51. The method of claim 48, wherein the oligonucleotide and the at least one anti-cancer agent is administered simultaneously.

52. The method of any one of claims 43-51, wherein the oligonucleotide is administered in combination with a radiation therapy.

53. The method of any one of claims 43-52, wherein the oligonucleotide is administered in combination with surgery.

54. The method of any one of claims 43-53, wherein the oligonucleotide is administered in combination with an allogenic stem cell transplant therapy.

55. The method of any one of claims 43-53, wherein the oligonucleotide is administered in combination with an autologous stem cell transplant therapy.

56. The method of any one of claims 43-55, wherein the individual has been previously treated for cancer with a therapy comprising chemotherapy, radiation therapy, surgery, or combinations thereof.

57. The method of any one of claims 43-56, wherein the metastatic cancer in the

individual relapsed after treatment with one or more of bortezomib,

cyclophosphamide, dexamethasone, doxorubicin, interferon-alpha, lenalidomide, melphalan, pegylated interferon-alpha, prednisone, thalidomide, and vincristine.

58. The method of any one of claims 43-57, wherein the cancer is a solid cancer.

59. The method of claim 58, wherein the solid cancer is bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, liver and bile duct cancer, lung cancer, melanoma, oral cancer, ovarian cancer, pancreatic cancer, pharynx cancer, prostate cancer, renal cancer, testicular cancer, or thyroid cancer.

60. The method of any one of claims 43-57, wherein the cancer is a non-solid cancer.

61. The method of claim 60, wherein the no n- solid cancer is multiple myeloma, leukemia, or lymphoma.

62. The method of any one of claims 43-61, wherein the oligonucleotide reduces the number of cancer stem cells in the individual as compared to an individual not administered the oligonucleotide.

63. The method of any one of claims 43-62, wherein the oligonucleotide inhibits tumor growth and/or metastasis in the individual as compared to an individual not administered the oligonucleotide.

64. A kit comprising one or more oligonucleotide complementary to an antisense non- coding chimeric mitochondrial RNA (ASncmtRNA) molecule or a sense non-coding chimeric mitochondrial RNA (SncmtRNA) molecule and instructions for practicing the methods of any one of clams 1-63.