Hedgehog antagonists, methods and uses related thereto

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.

We claim:  
     
         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.  
     
     
         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.  
     
     
         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.  
     
     
         16 . A method of  claim 14  or  15 , wherein said lung cell is present in the lung tissue of a premature infant.  
     
     
         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, AY 9944 , triparanol, compound B and functionally effective derivatives thereof.  
     
     
         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.