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1. WO2007106503 - TRAITEMENT COMBINÉ AVEC UN INHIBITEUR DE KINASE EGFR ET UN AGENT SENSIBILISANT LES CELLULES TUMORALES AUX EFFETS DES INHIBITEURS DE KINASE EGFR

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WHAT IS CLAIMED IS:

WHAT IS CLAIMED IS:

1. A method for manufacturing a medicament intended for treating NSCL, pancreatic, colon or breast cancer tumors or tumor metastases in combination with an EGFR kinase inhibitor, characterized in that an mTOR inhibitor is used, and wherein the inhibitors are intended for administration either simultaneously or sequentially.

2. The method of claim 1, wherein the medicament is intended for use in cancer.

3. The method of claim 1 or 2, wherein the EGFR kinase inhibitor and mTOR inhibitor are co-administered to the patient in the same formulation.

4. The method of claim 1 or 2, wherein the EGFR kinase inhibitor and mTOR inhibitor are co-administered to the patient in different formulations.

5. The method of any of claims 1-4, wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for co-administation to the patient by the same route.

6. The method of any of claims 1-4, wherein the EGFR kinase inhibitor and mTOR inhibitor are are intended for co-administation to the patient by different routes.

7. The method of any of claims 1-6, wherein the EGFR kinase inhibitor is a small organic molecule, an antibody or an antibody fragment that binds specifically to the EGFR.

8. The method of any of claims 1-6, wherein the EGFR kinase inhibitor comprises erlotinib, or a salt thereof.

9. The method of any of claims 1-8, additionally comprising the use of one or more other anti-cancer agents.

10. The method of any of claims 1-9, wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for administration simultaneously.

1 1. The method of any of claims 1 -9, wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for administration sequentially.

12. The method of any of claims 1-11, wherein the cells of the NSCL, pancreatic, colon or breast cancer tumors or tumor metastases have high sensitivity to growth inhibition by EGFR kinase inhibitors as single agents.

13. The method of any of claims 1-11, wherein the cells of the NSCL, pancreatic, colon or breast cancer tumors or tumor metastases have low sensitivity to growth inhibition by EGFR kinase inhibitors as single agents.

14. The method of any of claims 1-11, wherein the cells of the NSCL, pancreatic, colon or breast cancer tumors or tumor metastases have not undergone any form of EMT.

15. The method of any of claims 1-11, wherein the cells of the NSCL, pancreatic, colon or breast cancer tumors or tumor metastases have undergone an EMT.

16. A method for manufacturing a medicament intended for the treatment of NSCL, pancreatic, colon or breast cancer, characterized in that an amount of the EGFR kinase inhibitor, or a pharmaceutically acceptable salt thereof; and an amount of an mTOR inhibitor, or a pharmaceutically acceptable salt thereof are used; wherein at least one of the amounts is a sub-therapeutic amount.

17. The method of claim 16, wherein the EGFR kinase inhibitor comprises erlotinib, or a salt thereof..

18. The method of claim 16 or 17, additionally comprising the use of one or more other anti-cancer agents.

19. A method for manufacturing a medicament intended for treating NSCL, pancreatic, colon or breast cancer tumors or tumor metastases, characterized in that a synergistically effective therapeutic amount of a combination of an EGFR kinase inhibitor and an mTOR inhibitor are used, and wherein the inhibitors are intended for administration either simultaneously or sequentially.

20. The method of claim 19, wherein the EGFR kinase inhibitor comprises erlotinib, or a salt thereof.

21. The method of claim 19, additionally comprising the use of one or more other anti-cancer agents.

22. The method of any of claims 1-11, wherein the cells of the NSCL, pancreatic, colon or breast cancer tumors or tumor metastases are relatively insensitive or refractory to treatment with an EGFR inhibitor as a single agent.

23. The method of any of claims 16-18, wherein the NSCL, pancreatic, colon or breast cancer is relatively insensitive or refractory to treatment with an EGFR inhibitor as a single agent.

24. The method of any of claims 19-21, wherein the cells of the NSCL, pancreatic, colon or breast cancer tumors or tumor metastases are relatively insensitive or refractory to treatment with an EGFR inhibitor as a single agent.

25. A method for manufacturing a medicament intended for treating NSCL, pancreatic, colon or breast cancer tumors or tumor metastases, characterized in that a synergistically effective therapeutic amount of a combination of an EGFR kinase inhibitor and an mTOR inhibitor are used, wherein the inhibitors are intended for administration either simultaneously or sequentially, and wherein the medicament is intended for use after the steps of diagnosing a patient's likely responsiveness to an EGFR kinase inhibitor by assessing whether the tumor cells have undergone an epithelial-mesenchymal transition, and identifying the patient as one whose tumor or tumor metastases cells have undergone an epithelial-mesenchymal transition and are thus predicted to be relatively insensitive to an EGFR kinase inhibitor as a single agent, and thus likely to show an enhanced response in the presence of an mTOR inhibitor.

26. A method for manufacturing a medicament intended for treating NSCL, pancreatic, colon or breast cancer tumors or tumor metastases in a patient refractory to treatment with an EGFR kinase inhibitor as a single agent, characterized in that a synergistically effective therapeutic amount of a combination of an EGFR kinase inhibitor and an mTOR inhibitor are used, wherein the inhibitors are intended for administration either simultaneously or sequentially.

27. A method for manufacturing a medicament intended for treating tumors or tumor metastases in a patient in combination of an EGFR kinase inhibitor, characterized in that an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases is used, and wherein the inhibitors are intended for administration either simultaneously or sequentially.

28. The method of claim 27, wherein the medicament is intended for use in cancer.

29. The method of claim 27 or 28, wherein the EGFR kinase inhibitor and mTOR inhibitor are co-administered to the patient in the same formulation.

30. The method of claim 27 or 28, wherein the EGFR kinase inhibitor and mTOR inhibitor are co-administered to the patient in different formulations.

31. The method of any of claims 27-30, wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for co-administation by the same route.

32. The method of any of claims 27-30 wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for co-administation by different routes.

33. The method of any of claims 27-32, wherein the EGFR kinase inhibitor is a small organic molecule, an antibody or an antibody fragment that binds specifically to the EGFR.

34. The method of any of claims 27-32, wherein the EGFR kinase inhibitor comprises erlotinib, or a salt thereof.

35. The method of any of claims 27-34, additionally comprising the use of one or more other anti -cancer agents.

36. The method of any of claims 27-34, wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for administration simultaneously.

37. The method of any of claims 27-34, wherein the EGFR kinase inhibitor and mTOR inhibitor are intended for administration sequentially.

38. The method of any of claims 27-37, wherein the cells of the tumors or tumor metastases have high sensitivity to growth inhibition by EGFR kinase inhibitors as single agents.

39. The method of any of claims 27-37, wherein the cells of the tumors or tumor metastases have low sensitivity to growth inhibition by EGFR kinase inhibitors as single agents.

40. The method of any of claims 27-37, wherein the cells of the tumors or tumor metastases have not undergone any form of EMT.

41. The method of any of claims 27-37, wherein the cells of the tumors or tumor metastases have undergone an EMT.

42. A method for manufacturing a medicament intended for the treatment of cancer, characterized in that an amount of the EGFR kinase inhibitor, or a pharmaceutically acceptable salt thereof; and an amount of an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases, or a pharmaceutically acceptable salt thereof are used; wherein at least one of the amounts is administered as a subtherapeutic amount.

43. The method of claim 42, wherein the EGFR kinase inhibitor comprises erlotinib, or a salt thereof..

44. The method of claim 42 or 43, additionally comprising the use of one or more other anti -cancer agents.

45. A method for manufacturing a medicament intended for treating tumors or tumor metastases in a patient, characterized in that a synergistically effective therapeutic amount of a combination of an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases is used, and wherein the inhibitors are intended for administration either simultaneously or sequentially.

46. The method of claim 45, wherein the EGFR kinase inhibitor comprises erlotinib, or a salt thereof..

47. The method of claim 45, additionally comprising the use of one or more other anti-cancer agents.

48. The method of any of claims 27-37, wherein the cells of the tumors or tumor metastases are relatively insensitive or refractory to treatment with an EGFR inhibitor as a single agent.

49. The method of of any of claims 42-44, wherein the cancer is relatively insensitive or refractory to treatment with an EGFR inhibitor as a single agent.

50. The method of of any of claims 45-47, wherein the cells of the tumors or tumor metastases are relatively insensitive or refractory to treatment with an EGFR inhibitor as a single agent.

51. A method for manufacturing a medicament intended for treating tumors or tumor metastases, characterized in that a synergistically effective therapeutic amount of a combination of an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases are used, wherein the inhibitors are intended for administration either simultaneously or sequentially, and wherein the medicament is intended for use after the steps of diagnosing a patient's likely responsiveness to an EGFR kinase inhibitor by assessing whether the tumor cells have undergone an epithelial-mesenchymal transition, and identifying the patient as one whose tumor or tumor metastases cells have undergone an epithelial-mesenchymal transition and are thus predicted to be relatively insensitive to an EGFR kinase inhibitor as a single agent, and thus likely to show an enhanced response in the presence of an mTOR inhibitor.

52. A method for manufacturing a medicament intended for treating tumors or tumor metastases in a patient refractory to treatment with an EGFR kinase inhibitor as a single agent, characterized in that a synergistically effective therapeutic amount of a combination of an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases are used, wherein the inhibitors are intended for administration either simultaneously or sequentially.

53. A pharmaceutical composition comprising an EGFR kinase inhibitor and an mTOR inhibitor that binds to and directly inhibits both mTORCl and mT0RC2 kinases, in a pharmaceutically acceptable carrier.

54. The pharmaceutical composition of claim 53, wherein the EGFR kinase inhibitor in the composition comprises erlotinib.

55. The pharmaceutical composition of claim 53 or 54, additionally comprising one or more other anti -cancer agents.

56. A kit comprising a container, comprising an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases, and an EGFR kinase inhibitor.

57. The kit of claim 56, wherein the EGFR kinase inhibitor comprises erlotinib.

58. The kit of claim 56 or 57, further comprising a sterile diluent.

59. The kit of any of claims 56-58, further comprising a package insert comprising printed instructions directing the use of a combined treatment of an mTOR inhibitor that binds to and directly inhibits both mTORCl and mTORC2 kinases and erlotinib to a patient as a method for treating tumors, tumor metastases or other cancers in a patient.

60. The method of claim 27, wherein the patient is in need of treatment for a cancer selected from NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers.

61. The method of claim 42, wherein the cancer is selected from NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers.

62. The method of claim 45, wherein the patient is in need of treatment for a cancer selected from NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers.

63. The method of claim 51, wherein the patient is in need of treatment for a cancer selected from NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers.

64. The method of claim 52, wherein the patient is in need of treatment for a cancer selected from NSCLC, head and neck squamous cell carcinoma, pancreatic, breast and ovarian cancers.