Methods of treating pancreatic or liver cancer using hedgehog antagonists

• US 8,357,368 B2
• Filed: 04/08/2010
• Issued: 01/22/2013
• Est. Priority Date: 10/13/2000
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Dudek, Henryk, Karavanov, Irina, Pepicelli, Carmen, Kotkow, Karen, Rubin, Lee L.
• Primary Examiner(s): HOWARD, ZACHARY C
• Application Number:
  US12/756,939
• Publication Number:
  US 20110008333A1
• Time in Patent Office: 1,020 Days
• Field of Search: None
• US Class Current: 424/138.1
• 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: 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 treating a diseased or disordered tissue, comprising contacting said diseased or disordered tissue with an effective amount of a hedgehog antagonist;

wherein said diseased or disordered tissue has been determined to overexpress a gli-1 gene;

wherein said hedgehog antagonist is an anti-hedgehog antibody, which anti-hedgehog antibody binds Sonic hedgehog polypeptide and inhibits hedgehog signaling, or a small molecule, which small molecule is a veratrum-type steroidal alkaloid;

wherein the diseased or disordered tissue comprises a liver cancer or a pancreatic cancer; and

wherein contacting the diseased or disordered tissue with said hedgehog antagonist treats the diseased or disordered tissue.

2. The method of claim 1, wherein said diseased or disordered tissue comprises a liver cancer.

3. The method of claim 1, wherein said diseased or disordered tissue comprises a pancreatic cancer.

4. The method of claim 2 or 3, wherein said liver cancer or pancreatic cancer is a malignant tumor originating in the glandular epithelium.

5. The method of claim 4, wherein said malignant tumor is adenocarcinoma.

6. The method of claim 1, wherein said hedgehog antagonist is a veratrum-type steroidal alkaloid small molecule, which small molecule has a molecular weight less than 2000 daltons.

7. The method of claim 6, wherein said small molecule is cyclopamine.

8. The method of claim 1, wherein said anti-hedgehog antibody is a monoclonal antibody.

9. The method of claim 8, wherein said anti-hedgehog antibody is a humanized antibody.

10. The method of claim 1, wherein said hedgehog antagonist is formulated in a pharmaceutically acceptable carrier.

11. The method of claim 1, wherein said hedgehog antagonist is administered as part of a cancer treatment regimen.

12. The method of claim 1, wherein contacting said tissue with said hedgehog antagonist inhibits at least one of unwanted growth, proliferation or survival of cells of the diseased or disordered tissue.

13. The method of claim 1, wherein gli-1 gene overexpression was determined by gli-1 transcript expression.

14. The method of claim 1, wherein gli-1 gene overexpression was determined by gli-1 protein expression.

15. The method of claim 1, wherein gli-1 gene overexpression was determined by obtaining a tissue sample from a patient, and determining whether said sample overexpresses said gli-1 gene.

16. The method of claim 1, wherein the antibody is 5E1 or an antibody which binds the same epitope as 5E1.

17. A method of treating a diseased or disordered tissue, comprising contacting a diseased or disordered tissue with an effective amount of a hedgehog antagonist;

wherein said diseased or disordered tissue has been determined to overexpress Sonic hedgehog;

wherein said hedgehog antagonist is an anti-hedgehog antibody, which anti-hedgehog antibody binds Sonic hedgehog polypeptide and inhibits hedgehog signaling, or a small molecule, which small molecule is a veratrum-type steroidal alkaloid;

wherein the diseased or disordered tissue comprises a liver cancer or pancreatic cancer; and

wherein contacting the diseased or disordered tissue with said hedgehog antagonist treats the diseased or disordered tissue.

18. The method of claim 17, wherein Sonic hedgehog overexpression is determined by obtaining a tissue sample from a patient, and determining whether said sample overexpresses Sonic hedgehog.

19. A method of treating a diseased or disordered tissue in a patient in need thereof, comprising contacting said diseased or disordered tissue with an effective amount of an anti-hedgehog antibody;

wherein said diseased or disordered tissue has been determined to overexpress Sonic hedgehog;

wherein said anti-hedgehog antibody binds Sonic hedgehog polypeptide and inhibits hedgehog signaling;

wherein the diseased or disordered tissue comprises a liver cancer or a pancreatic cancer;

and wherein contacting the diseased or disordered tissue with said anti-hedgehog antibody decreases unwanted cell proliferation and treats the diseased or disordered tissue in said patient in need thereof.

20. A method of treating a diseased or disordered tissue, comprising contacting a diseased or disordered tissue with an effective amount of an anti-hedgehog antibody, which anti-hedgehog antibody is 5E1 or an antibody which binds the same epitope as 5E1;

wherein said diseased or disordered tissue has been determined to overexpress Sonic hedgehog;

wherein the diseased or disordered tissue comprises a liver cancer or a pancreatic cancer;

and wherein contacting the diseased or disordered tissue with said anti-hedgehog antibody decreases unwanted cell proliferation and treats the diseased or disordered tissue.

21. A method of treating a liver or pancreatic cancer in a patient in need thereof, comprising contacting a diseased or disordered tissue of said patient comprising a liver cancer or a pancreatic cancer with an effective amount of a hedgehog antagonist;

wherein said hedgehog antagonist is an anti-hedgehog antibody, which anti-hedgehog antibody binds Sonic hedgehog polypeptide and inhibits hedgehog signaling, or a small molecule, which small molecule is a veratrum-type steroidal alkaloid; and

wherein the diseased or disordered tissue comprising said liver cancer or said pancreatic cancer has been determined to overexpress Sonic hedgehog.

22. A method of treating a liver or pancreatic cancer in a patient in need thereof, comprising administering to said patient in need thereof an amount of a hedgehog antagonist sufficient to decrease at least one of the growth or proliferation of liver or pancreatic cancer tissue;

wherein said hedgehog antagonist is an anti-hedgehog antibody, which anti-hedgehog antibody binds Sonic hedgehog polypeptide and inhibits hedgehog signaling, or a small molecule, which small molecule is a veratrum-type steroidal alkaloid;

and wherein the liver or pancreatic cancer tissue has been determined to overexpress Sonic hedgehog.

23. A method of treating a diseased or disordered tissue in a patient in need thereof, comprising administering to said patient in need thereof an amount of a hedgehog antagonist effective to decrease at least one of the growth or proliferation of the diseased or disordered tissue;

wherein the hedgehog antagonist is an anti-hedgehog antibody;

wherein said anti-hedgehog antibody binds Sonic hedgehog polypeptide and inhibits hedgehog signaling;

wherein the diseased or disordered tissue comprises a liver cancer or a pancreatic cancer;

and wherein the diseased or disordered tissue has been determined to overexpress a gli-1 gene or a Sonic hedgehog gene.

24. The method of claim 23, wherein the antibody is 5E1 or an antibody which binds the same epitope as 5E1.