Hedgehog antagonists, methods and uses related thereto

• US 20040110663A1
• Filed: 08/29/2003
• Published: 06/10/2004
• Est. Priority Date: 10/13/2000
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Dudek, Henryk, Karavanov, Irina, Pepicelli, Carmen, Rubin, Lee L., Kotkow, Karen
• Granted Patent: US 7,708,998 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• 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: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 14/46 from vertebrates
• 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 at least one of unwanted growth, proliferation or survival of a cell, comprising

(a) determining whether said cell expresses a gli gene, and

(b) contacting said cell which expresses a gli gene with an effective amount of a hedgehog antagonist;

wherein contacting said cell with said hedgehog antagonist decreases at least one of cell growth, proliferation or survival.

2. A method of claim 1, wherein said gli gene is gli-1.

3. A method of claim 1, wherein said unwanted cell proliferation is cancer.

4. A method of claim 3, wherein said cancer is urogenital cancer.

5. A method of claim 3, wherein said cancer is associated with one or more of lung, prostate, breast, ovary, uterus, muscle, bladder, colon, kidney, pancreas, and liver tissues.

6. A method of claim 5, wherein said form of cancer associated with breast tissue is selected from inferior ductal carcinoma, inferior lobular carcinoma, intraductal carcinoma, medullary carcinoma and tubular carcinoma.

7. A method of claim 5, wherein said cancer associated with lung tissue is selected from adenocarcinoma, broncho-alveolar adenocarcinoma and small cell carcinoma.

8. A method of claim 5, wherein said cancer associated with the prostate is adenocarcinoma.

9. A method of claim 1, wherein said unwanted cell proliferation is benign prostatic hyperplasia.

17. A method of any one of claims 1-13, wherein said hedgehog antagonist is selected from a small molecule having a molecular weight less than 2000 daltons, a hedgehog antibody, a patched antibody, a smoothened antibody, a mutant hedgehog protein, an antisense nucleic acid, an RNAi construct, or a ribozyme.

18. A method of claim 17, wherein said small molecule is selected from cyclopamine, compound A, tomatidine, jervine, AY9944, triparanol, compound B and functionally effective derivatives thereof.

10. A method for determining a treatment protocol comprising,

obtaining a tissue sample from a patient, and

determining levels of gli gene expression in said sample,

wherein overexpression of a gli gene indicates that treatment with a hedgehog antagonist is appropriate.

11. A method of claim 10, wherein said gli gene is gli-1.

12. A method of claim 11, wherein gli-1 expression levels are determined by measuring gli-1 transcript levels.

13. A method of claim 11, wherein said gli-1 levels are determined by measuring gli-1 protein levels.

14. A method of stimulating surfactant production in a lung cell comprising contacting said cell with an amount of hedgehog antagonist effective to stimulate surfactant production.

16. A method of claim 14 or 15, wherein said lung cell is present in the lung tissue of a premature infant.

15. A method of stimulating lamellated body formation in a lung cell comprising contacting said cell with an amount of hedgehog antagonist effective to stimulate lamellated body formation.

19. A method of determining the likelihood that a cancer will develop in a tissue, comprising obtaining a tissue sample, and

determining levels of gli gene expression in said sample,

wherein overexpression of a gli gene indicates an increased likelihood that cancer will develop.

20. A method of claim 19, wherein said gli gene is gli-1.

21. A method for treating a tumor in a patient, comprising administering to said patient an amount of a hedgehog antagonist sufficient to decrease at least one of the growth, proliferation or survival of the tumor, wherein the tumor expresses at least one of a hedgehog gene or a gli gene.

22. The method of claim 21, wherein hedgehog antagonist is administered as part of a cancer treatment regimen.

23. A method of inhibiting at least one of unwanted growth, proliferation or survival of a cell, comprising

(a) determining whether said cell expresses a hedgehog gene, and

(b) contacting said cell which expresses said hedgehog gene with an effective amount of a hedgehog antagonist;

wherein contacting said cell with said hedgehog antagonist decreases at least one of cell growth, proliferation or survival.

24. The method of claim 23, wherein said hedgehog gene is Sonic hedgehog.

25. The method of claim 23, wherein said hedgehog antagonist is a hedgehog antibody.

26. The method of claim 25, wherein said hedgehog antibody is a monoclonal antibody.

27. The method of claim 26, wherein said monoclonal antibody is selected from 5E1 or a monoclonal antibody which binds the same epitope as 5E1.

28. The method of claim 23, wherein said unwanted cell growth, proliferation or survival of a cell is cancer.

29. A method of inhibiting at least one of unwanted cell growth, proliferation or survival of a cell, comprising

(a) determining whether cells express a hedgehog gene, and

(b) contacting cells which express said hedgehog gene with an effective amount of a hedgehog antibody, which hedgehog antibody specifically antagonizes hedgehog signaling;

wherein contacting said cells with said hedgehog antibody decreases at least one of cell growth, proliferation or survival.

30. The method of claim 29, wherein said hedgehog antibody which specifically antagonizes hedgehog signaling is a monoclonal antibody.

31. The method of claim 30, wherein said monoclonal antibody is 5E1 or a monoclonal antibody which binds the same epitope as 5E1.

32. The method of claim 29, wherein said unwanted cell growth, proliferation or survival of a cell is cancer.

33. The method of claim 29, wherein said hedgehog antibody which antagonizes hedgehog signaling is formulated in a pharmaceutically acceptable carrier.

34. The method of claim 32, wherein said hedgehog antibody is administererd as part of a cancer treatment regimen.

35. A method of inhibiting at least one of unwanted cell growth, proliferation or survival of a cell, comprising

(a) determining whether said cell expresses a hedgehog gene, and

(b) contacting said cell which expresses said hedgehog gene with an effective amount of a hedgehog antibody, which hedgehog antibody is 5E1 or an antibody which binds the same epitope as 5E1;

wherein contacting said cell with said hedgehog antibody decreases at least one of cell growth, proliferation or survival.

36. The method of claim 35, wherein said unwanted cell growth, proliferation or survival of a cell is cancer.

37. The method of claim 35, wherein said hedgehog antibody which antagonizes hedgehog signaling is formulated in a pharmaceutically acceptable carrier.

38. The method of claim 35, wherein said hedgehog antibody is administererd as part of a cancer treatment regimen.

39. A method for treating a tumor is a patient, comprising administering to said patient an amount of a hedgehog antagonist effective to decrease at least one of the growth, proliferation or survival of said tumor.

40. The method of claim 39, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

41. The method of claim 39, wherein said hedgehog antagonist comprises a hedgehog antibody.

42. The method of claim 41, wherein said hedgehog antibody comprises a monoclonal antibody.

43. The method of claim 42, wherein said monoclonal antibody comprises 5E1 or an antibody which binds the same epitope as 5E1.

44. The method of claim 39, wherein said hedgehog antagonist is formulated in a pharmaceutically acceptable carrier.

45. Use of a hedgehog antagonist in the manufacture of a medicament for treating a tumor in a patient.

46. The use according to claim 45, wherein the hedgehog antagonist is administered as part of a cancer treatment regimen.

47. The use according to claim 45, wherein the hedgehog antagonist is a hedgehog antibody.

48. Use of a hedgehog antagonist in the manufacture of a medicament for inhibiting at least one of unwanted growth, proliferation or survival of a cell.

49. The use according to claim 48, wherein the hedgehog antagonist is administered as part of a cancer treatment regimen.

50. The use according to claim 48, wherein the hedgehog antagonist is a hedgehog antibody.