Screening for anti-cancer compounds using netrin-1 activity

Abstract

The subject matter of the present invention relates to an in vitro method for the screening of anti-cancer compounds based on the capacity for these compound to interact with netrin-1 receptor and/or to inhibit the dimerization of the intracellular domain of the netrin-1 receptor expressed in tumor cells. The invention also relates to a method for predicting the presence of metastatic or aggressive cancer, or for determining the efficiency of an anti-cancer treatment based on the measuring of the expression level of netrin-1. The invention further comprises kits and compounds as a medicament for the treatment of cancer such as metastatic breast cancer, related to the overexpression of netrin-1 by the tumor cells.

1 .- 38 . (canceled) 
     
     
         39 . A method of treatment for inducing the apoptosis or the cell death of tumor cells which has acquired the selective advantage to escape netrin-1 dependence receptors induced apoptosis by elevated netrin-1 level, in a patient having such tumor cells, comprising
 administering to said patient an effective amount of a monoclonal or polyclonal antibody directed specifically against netrin-1, a netrin-1 receptor or an extracellular domain of a netrin-1 receptor, which antibody specifically inhibits the interaction between the netrin-1 and a netrin-1 receptor and/or the dimerization or multimerization of a netrin-1 receptor or of the intracellular domain of a netrin-1 receptor.   
     
     
         40 . The method of  claim 39 , comprising the step of identifying a patient suffering from a cancer having tumoral cells expressing or overexpressing netrin 1. 
     
     
         41 . The method of  claim 39 , wherein the antibody is a chimeric antibody or a humanized antibody. 
     
     
         42 . The method of  claim 39 , comprising administering to said patient an effective amount of a monoclonal or polyclonal antibody directed specifically against netrin-1. 
     
     
         43 . The method of  claim 42 , wherein the antibody is a chimeric antibody or a humanized antibody. 
     
     
         44 . The method of  claim 39 , wherein the netrin-1 receptor is Deleted in Colorectal Cancer (DCC). 
     
     
         45 . The method of  claim 39 , wherein the netrin-1 receptor is UNC5H. 
     
     
         46 . The method of  claim 45 , wherein the netrin-1 receptor UNC5H is selected from the group consisting of UNC5H1, UNC5H2 and UNC5H3. 
     
     
         47 . The method of  claim 39 , wherein the netrin-1 receptor is neogenin. 
     
     
         48 . The method of  claim 39 , wherein the netrin-1 receptor is adenosine A2b. 
     
     
         49 . The method of  claim 39 , for the prevention or the treatment of cancer in mammals, including man, wherein the cancer has tumoral cells expressing said netrin-1 receptor and expressing or overexpressing netrin-1. 
     
     
         50 . The method of  claim 39 , wherein said cancer is a metastatic or an aggressive cancer. 
     
     
         51 . The method of  claim 39 , wherein said cancer is selected from the group consisting of breast cancer, colorectal cancer, lung cancer, neuroblastoma, glioma, acute myeloid leukemia, sarcoma, melanoma, ovarian adenocarcinoma, renal adenocarcinoma pancreatic adenocarcinoma, uterus adenocarcinoma, stomach adenocarcinoma, kidney adenocarcinoma and rectal adenocarcinoma. 
     
     
         52 . The method of  claim 39 , wherein the primary tumor cells of said cancer express or overexpress netrin-1. 
     
     
         53 . The method of  claim 39 , wherein said cancer is breast cancer. 
     
     
         54 . The method of  claim 39 , wherein said cancer is colorectal cancer. 
     
     
         55 . A method of anti-cancer treatment for inducing the apoptosis or the cell death of tumor cells expressing or overexpressing netrin-1, in a patient having such tumor cells, comprising
 administering to said patient an effective amount of a monoclonal or polyclonal antibody directed specifically against netrin-1, a netrin-1 receptor or an extracellular domain of a netrin-1 receptor, which antibody specifically inhibits the interaction between the netrin-1 and a netrin-1 receptor and/or the dimerization or multimerization of a netrin-1 receptor or of the intracellular domain of a netrin-1 receptor.   
     
     
         56 . The method of  claim 55 , comprising identifying a patient having a metastatic or an aggressive cancer which has a netrin-1 expression level increased by a ratio superior to 2 with respect to a non-metastatic or non-aggressive reference biopsy. 
     
     
         57 . The method of  claim 56 , wherein the ratio is superior to 3. 
     
     
         58 . The method of  claim 56 , wherein the ratio is superior to 4. 
     
     
         59 . The method of  claim 56 , wherein the ratio is superior to 5.