METHODS OF INHIBITING UNWANTED CELL PROLIFERATION USING HEDGEHOG ANTAGONISTS

• US 20110076286A1
• Filed: 06/01/2010
• Published: 03/31/2011
• Est. Priority Date: 10/13/2000
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Dudek, Henryk, Karavanov, Irina, Pepicelli, Carmen
• Granted Patent: US 8,486,400 B2
• Time in Patent Office: Days
• US Class Current: 424/174.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07J 69/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
• CPC Class Codes: C07J 71/0005 Oxygen-containing hetero ring
• CPC Class Codes: C07J 71/0068 at position 16(17)
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/3038 Kidney, bladder
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: G01N 33/574 for cancer

Abstract

The present application is directed to compositions and methods for inhibiting angiogenesis and treating or preventing unwanted cell proliferation, including tumors, by inhibiting the hedgehog pathway, e.g., with an antagonist of the hedgehog pathway such as those disclosed herein.

Claims

1. A method of inhibiting unwanted cell proliferation associated with cancer in a tissue comprising,

determining whether said tissue overexpresses a gli-1 gene, and

contacting said tissue that overexpresses a gli-1 gene with an effective amount of a hedgehog antibody, which hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling;

whereby said hedgehog antibody causes decreased cell proliferation in the tissue, and

wherein the cancer is associated with one or more of prostate, breast, bladder, or colon tissues.

2. The method of claim 1, wherein said cancer is associated with one or more of bladder or colon tissues.

3. A method of claim 1, wherein said form of cancer is associated with breast tissue and is selected from inferior ductal carcinoma, inferior lobular carcinoma, intraductal carcinoma, medullary carcinoma and tubular carcinoma.

4. A method of claim 1 , wherein said cancer associated with the prostate is adenocarcinoma.

6. The method of claim 1, wherein said cancer is associated with one or more of breast or colon tissues.

7. The method of claim 1, wherein said cancer is associated with colon tissues.

9. The method of claim 1, wherein said cancer is associated with one or more of prostate or colon tissues.

23. The method of claim 1, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

24. The method of claim 1, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

25. The method of claim 2, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

26. The method of claim 2, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

5. A method for treating a tumor in a patient, comprising determining whether the tumor overexpresses a gli-1 gene and administering to said patient an amount of a hedgehog antibody sufficient to decrease at least one of the growth or proliferation of the tumor, which hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling, wherein the tumor overexpresses a gli-1 gene and wherein the tumor is associated with at least one of urogenital, lung, breast, prostate, bladder, or colon cancer.

8. The method of claim 5, wherein said tumor is associated with at least one of urogenital, breast, prostate, bladder, or colon tissues.

10. The method of claim 5, wherein said tumor is associated with colon tissue.

11. The method of claim 5, wherein said tumor is associated with at least one of breast, prostate, bladder, or colon tissues.

12. The method of claim 5, wherein said tumor is associated with at least one of breast or colon tissues.

13. The method of claim 5, wherein said tumor is associated with at least one of bladder or colon tissues.

14. The method of claim 5, wherein said tumor is associated with at least one of prostate or colon tissues.

18. The method of claim 5, wherein determining whether the tumor overexpresses a gli-1 gene comprises obtaining a sample of said tumor, and determining whether said sample overexpresses said gli-1 gene, wherein overexpression of said gli-1 gene in said sample indicates that administration of said hedgehog antagonist is appropriate.

19. The method of claim 11, wherein determining whether the tumor overexpresses a gli-1 gene comprises obtaining a sample of said tumor, and determining whether said sample overexpresses said gli-1 gene, wherein overexpression of said gli-1 gene in said sample indicates that administration of said hedgehog antagonist is appropriate.

20. The method of claim 12, wherein determining whether the tumor overexpresses a gli-1 gene comprises obtaining a sample of said tumor, and determining whether said sample overexpresses said gli-1 gene, wherein overexpression of said gli-1 gene in said sample indicates that administration of said hedgehog antagonist is appropriate.

21. The method of claim 13, wherein determining whether the tumor overexpresses a gli-1 gene comprises obtaining a sample of said tumor, and determining whether said sample overexpresses said gli-1 gene, wherein overexpression of said gli-1 gene in said sample indicates that administration of said hedgehog antagonist is appropriate.

22. The method of claim 14, wherein determining whether the tumor overexpresses a gli-1 gene comprises obtaining a sample of said tumor, and determining whether said sample overexpresses said gli-1 gene, wherein overexpression of said gli-1 gene in said sample indicates that administration of said hedgehog antagonist is appropriate.

33. The method of claim 18, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

34. The method of claim 18, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

35. The method of claim 19, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

36. The method of claim 19, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

37. The method of claim 20, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

38. The method of claim 20, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

39. The method of claim 21, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

40. The method of claim 21, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

41. The method of claim 22, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

42. The method of claim 22, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

15. A method for treating colon cancer, comprising

determining whether colon cancer tissue overexpresses a gli-1 gene and

administering to a patient in need thereof an amount of a hedgehog antibody sufficient to decrease at least one of the growth or proliferation of the colon cancer tissue, wherein the colon cancer tissue overexpresses a gli-1 gene, and wherein the hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling.

17. The method of claim 15, wherein determining whether said tissue overexpresses a gli-1 gene comprises obtaining a tissue sample from a patient, and determining whether said sample overexpresses said gli-1 gene, wherein overexpression of said gli-1 gene in said sample indicates that administration of said hedgehog antagonist is appropriate.

27. The method of claim 15, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

28. The method of claim 15, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

31. The method of claim 17, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

32. The method of claim 17, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

16. A method of inhibiting unwanted cell proliferation in colon cancer tissue comprising,

determining whether said tissue overexpresses a gli-1 gene, and

contacting said tissue that overexpresses a gli-1 gene with an effective amount of a hedgehog antibody, which hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling;

whereby said hedgehog antibody causes decreased cell proliferation in the colon cancer tissue.

29. The method of claim 16, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 transcript expression.

30. The method of claim 16, wherein determining whether said tissue overexpresses a gli-1 gene comprises determining gli-1 protein expression.

43. A method for treating colon cancer in a patient in need thereof, comprising ascertaining whether colon cancer tissue overexpresses a gli-1 gene, and administering to said patient in need thereof an amount of a hedgehog antibody sufficient to decrease at least one of the growth or proliferation of the colon cancer tissue, wherein the hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling, and wherein the colon cancer tissue overexpresses a gli-1 gene.

44. A method for treating a tumor in a patient, comprising determining whether the tumor overexpresses a Sonic hedgehog gene and administering to said patient an amount of a hedgehog antibody sufficient to decrease at least one of the growth or proliferation of the tumor, which hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling, wherein the tumor overexpresses a Sonic hedgehog gene and wherein the tumor is associated with at least one of urogenital, breast, prostate, bladder, or colon cancer.

45. The method of claim 44, wherein said tumor is associated with colon tissue.

52. The method of claim 44, wherein the tumor is associated with at least one of breast or colon cancer.

46. A method for treating colon cancer in a patient in need thereof, comprising ascertaining whether colon cancer tissue overexpresses a Sonic hedgehog gene and administering to said patient in need thereof an amount of a hedgehog antibody sufficient to decrease at least one of the growth or proliferation of the colon cancer tissue, wherein the hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling, and wherein the colon cancer tissue overexpresses a Sonic hedgehog gene.

47. A method for treating a tumor in a patient in need thereof, comprising ascertaining whether the tumor overexpresses a Sonic hedgehog gene, and administering to said patient in need thereof an amount of a hedgehog antibody sufficient to decrease at least one of the growth or proliferation of the tumor, which hedgehog antibody binds to Sonic hedgehog protein and inhibits hedgehog signaling, wherein the tumor overexpresses a Sonic hedgehog gene, and wherein the tumor is associated with at least one of urogenital, breast, prostate, bladder, or colon cancer.

48. The method of claim 47, wherein the tumor is associated with at least one of urogenital, prostate, bladder, or colon cancer.

49. The method of claim 47, wherein the tumor is associated with at least one of breast, prostate, bladder, or colon cancer.

50. The method of claim 47, wherein the tumor overexpresses a Sonic hedgehog gene.

51. The method of claim 47, wherein the tumor is associated with colon cancer.

53. The method of claim 47, wherein the tumor is associated with at least one of breast or colon cancer.