Method for using cdo antagonists to modulate hedgehog signaling

Abstract

The present invention provides for a method of using BOC/CDO hedgehog antagonists to inhibit hedgehog signaling, as well as treating and diagnosing disorders relating to hedgehog signaling or overexpression of hedgehog, including cancer, cell proliferative disorders, and angiogenesis, neurological disorders, as well as other conditions affected by hedgehog signaling such as hair growth, neural stem cell differentiation, chondrogenesis and osteogenesis, lung surfactant production, formation of lamellated bodies in lung cells.

1 . A method for inhibiting the interaction of Sonic hedgehog, Desert hedgehog, or Indian hedgehog with Patched-1 or Patched-2 in a cell that expresses Patched-1 or Patched-2, comprising contacting said cell with an effective amount of a CDO antagonist. 
     
     
         2 . The method of  claim 1 , wherein the CDO antagonist causes inhibition of the growth of the cell. 
     
     
         3 . The method of  claim 1 , wherein the CDO antagonist causes the death of the cell. 
     
     
         4 . The method of  claim 1 , wherein the cell is a cancer cell. 
     
     
         5 . The method of  claim 1 , wherein the CDO antagonist is an anti-CDO antibody. 
     
     
         6 . The method of  claim 5 , wherein the anti-CDO antibody specifically binds to a polypeptide comprising the amino acid sequence of SEQ ID NO:4. 
     
     
         7 . The method of  claim 1 , wherein the CDO antagonist is a CDO RNAi. 
     
     
         8 . The method of  claim 1 , wherein the CDO antagonist is conjugated to a growth inhibitory agent or cytotoxic agent. 
     
     
         9 . The method of  claim 8 , wherein the growth inhibitory agent or cytotoxic agent is selected from the group consisting of: a maytansinoid, a calicheamicin, an antibiotic, a radioactive isotope, and a nucleolytic enzyme. 
     
     
         10 . A method of therapeutically treating a mammal having a cancerous tumor comprising cells that express a hedgehog polypeptide, wherein the method comprises administering to the mammal a therapeutically effective amount of a CDO antagonist that binds to the hedgehog polypeptide, thereby resulting in the effective treatment of the tumor. 
     
     
         11 . The method of  claim 10 , wherein the CDO antagonist is selected from the group consisting of: an anti-CDO antibody, a CDO-binding antibody fragment, an antagonist CDO chimeric polypeptide, a CDO binding oligopeptide, a CDO sense/antisense nucleic acid, a CDO binding small organic molecule, and a CDO RNAi. 
     
     
         12 . The method of  claim 11 , wherein the CDO antagonist, respectively, is conjugated to a growth inhibitor agent or cytotoxic agent selected from the group consisting of: a maytansinoid, a calicheamicin, an antibiotic, a radioactive isotope, nucleolytic enzyme. 
     
     
         13 . A method of diagnosing the presence of a tumor in a mammal, comprising (a) contacting a test sample comprising tissue or cells obtained from the mammal with a molecule that binds to a CDO polypeptide; (b) detecting the formation of a complex between the CDO-binding molecule and the CDO polypeptide in the test sample, wherein the formation of more complex in the sample relative to a control sample is indicative of the presence of a tumor in the mammal. 
     
     
         14 . The method of  claim 13 , wherein the CDO-binding molecule employed is detectably labeled or attached to a solid support. 
     
     
         15 . The method of  claim 13 , wherein the test sample of tissue or cells is obtained from an individual suspected of having a cancerous tumor. 
     
     
         16 . A method of inhibiting the growth of a cancer cell, wherein the growth of said cancer cell is at least in part dependent upon the growth potentiating effect(s) of a hedgehog polypeptide and the modulation thereof by a CDO polypeptide, wherein the method comprises contacting the hedgehog polypeptide with a CDO antagonist that binds to the hedgehog or CDO polypeptide, thereby antagonizing the growth potentiating activity of the hedgehog polypeptide, and inhibiting the growth of the cancer cell. 
     
     
         17 . The method of  claim 16 , wherein the binding of the CDO antagonist to the hedgehog or CDO polypeptide induces the death of the cancer cell. 
     
     
         18 . The method of  claim 16 , wherein the CDO antagonist is an anti-CDO antibody, a CDO-binding antibody fragment, an antagonist CDO chimeric polypeptide, a CDO binding oligopeptide, a CDO sense/antisense nucleic acid, a CDO binding organic molecule, or a CDO RNAi. 
     
     
         19 . The method of  claim 18 , wherein the CDO antagonist is conjugated to a growth inhibitory agent or cytotoxic agent. 
     
     
         20 . The method of  claim 19 , wherein the growth inhibitory agent is selected from the group consisting of a maytansinoid, a calicheamicin, an antibiotic, a radioactive isotope, and a nuclelytic enzyme. 
     
     
         21 . A method of therapeutically treating a tumor in a mammal, wherein the growth of said tumor is at least in part dependent upon the growth potentiating effect(s) of a hedgehog polypeptide and the modulation thereof by a CDO polypeptide, comprising administering to the mammal a therapeutically effective amount of a CDO antagonist that binds to the hedgehog or CDO polypeptide, thereby antagonizing the growth potentiating activity of the hedgehog polypeptide and resulting in the effective therapeutic treatment of the tumor. 
     
     
         22 . The method of  claim 21 , wherein the CDO antagonist is an anti-CDO antibody, a CDO-binding antibody fragment, an antagonist CDO chimeric polypeptide, a COD binding oligopeptide, a CDO sense/antisense nucleic acid, a CDO binding organic molecule, or a CDO RNAi. 
     
     
         23 . The method of  claim 22 , wherein the CDO antagonist is conjugated to a growth inhibitory agent or cytotoxic agent. 
     
     
         24 . The method of  claim 23 , wherein the growth inhibitory agent is selected from the group consisting of a maytansinoid, a calicheamicin, an antibiotic, a radioactive isotope, and a nuclelytic enzyme. 
     
     
         25 . A method of treating cancer comprising contacting a cancer cell or tissue with an effective amount of a CDO antagonist. 
     
     
         26 . The method of  claim 25 , wherein the cancer is a cancer of the neuronal system. 
     
     
         27 . The method of  claim 25 , wherein the cancer is a cancer of breast tissue. 
     
     
         28 . The method of  claim 25 , wherein the cancer is associated with lung tissue.