Hedgehog antagonists, methods and uses related thereto

• US 20040060568A1
• Filed: 10/15/2001
• Published: 04/01/2004
• Est. Priority Date: 10/13/2000
• Status: Abandoned Application

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Pepicelli, Carmen, Dudek, Henryk, Karavanov, Irina
• Application Number:
  US09/977,864
• Publication Number:
  US 20040060568A1
• Time in Patent Office: Days
• US Class Current: 128/898
• 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 comprising,

determining whether cells overexpress a gli gene, and

contacting cells that overexpress a gli gene with an effective amount of a hedgehog antagonist;

whereby said antagonist causes decreased cell proliferation.

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, bladder, and colon 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 1-15, 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, and 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 the grow and/or proliferation of the tumor, wherein the tumor is associated with at least one of urogenital, lung, breast, prostate, bladder, or colon cancer.

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