Suppression of inhibitors

Abstract

The present invention relates to methods for inhibiting malignant tumour growth, invasion and/or metastasis in a patient, the method comprising suppressing the inhibitory activity of an inhibitor of a protease or of a non-proteolytic matrix-degrading enzyme (IPNME) in malignant tumour tissue or potential malignant tumour tissue. The suppression may be brought about by administering compounds interacting with the IPNME, but also administration of compounds interacting with transcription of genes encoding the IPNME is a possibility. The invention also relates to methods of selecting and identifying compounds in the therapeutical methods, as well of the use of such compounds in the treatment of malignancies.

1 . A method of inhibiting malignant tumor growth, invasion and/or metastasis in a subject, said malignant tumor growth, invasion and/or metastasis being associated with activity in malignant tumor tissue of an inhibitor of a metalloprotease, which comprises administering to the subject a suppressive amount of a suppressor of said metalloprotease inhibitor, whereby malignant tumor growth, invasion and/or metastasis is inhibited. 
     
     
         2 . The method of  claim 1  in which the suppressor is an antibody which specifically binds to and inhibits said metalloprotease inhibitor. 
     
     
         3 . The method of  claim 2  in which the antibody is a monoclonal antibody. 
     
     
         4 . The method of  claim 1  wherein the metalloprotease inhibitor is TIMP-1 or TIMP-2. 
     
     
         5 . The method of  claim 2  wherein the metalloprotease inhibitor is TIMP-1 or TIMP-2. 
     
     
         6 . The method of  claim 5  in which the metalloprotease inhibitor is TIMP-1. 
     
     
         7 . The method of  claim 5  in which the metalloprotease inhibitor is TIMP-2. 
     
     
         8 . The method of  claim 1 , wherein as a result of the suppression of the inhibitor activity of the inhibitor of the metalloprotease in malignant tumor tissue, the metalloprotease degrades the malignant tumor tissue. 
     
     
         9 . The method of  claim 1 , wherein the suppression of the inhibitory activity of the inhibitor of the metalloprotease in malignant tumor tissue results in interference with the process of tumor angiogenesis, said process being one promoted by said metalloprotease inhibitor. 
     
     
         10 . The method of  claim 1 , wherein the suppression of the inhibitory activity of the inhibitor of the metalloprotease in malignant tumor tissue results in interference with the migrating capacity of malignant tumor cells or of other cells in the tumor stroma. 
     
     
         11 . The method of  claim 1 , wherein the patient has a carcinoma in situ. 
     
     
         12 . The method of  claim 1 , wherein the patient has an increased concentration of the inhibitor of the metalloprotease in a sample obtained from the group consisting of malignant tumor tissue, plasma, and serum. 
     
     
         13 . The method of  claim 1 , wherein the patient has an increased concentration of the inhibitor of the metalloprotease in a sample obtained from the group consisting of malignant tumor tissue, plasma, and serum, and the increased concentration of the inhibitor of the metalloprotease has been established to be a prognostic factor indicating a poor prognosis for the patient having the type of malignant tumor in question. 
     
     
         14 . The method of  claim 1 , wherein the patient has an increased concentration of the inhibitor of the metalloprotease in a sample obtained from the group consisting of malignant tumor tissue, plasma, and serum, and the increased concentration of the inhibitor of the metalloprotease may be established to be a predictive factor indicating efficiency of the treatment of the type of malignant tumor in question by suppressing the said inhibitor. 
     
     
         15 . The method of  claim 1 , wherein the malignant tumor is selected from the group consisting of a mammary carcinoma, a urological carcinoma, a gynecological carcinoma, a non-small cell lung tumor, gastrointestinal cancer, a brain tumor, a sarcoma, a haematological malignancy, and skin cancer. 
     
     
         16 . The method of  claim 1  wherein the method is performed prior to surgery to remove malignant tumor tissue. 
     
     
         17 . The method of  claim 1  wherein the method is performed after surgery to remove malignant tumor tissue. 
     
     
         18 . The method of  claim 1  in which the suppressor is a peptide which can be expressed on the surface of filamentous phage in a combinatorial filamentous phage library, and which when so expressed, binds to TIMP-1 or TIMP-2. 
     
     
         19 . A method of suppressing the inhibitory activity of a metalloprotease inhibitor in malignant tumor tissue of a subject, which comprises contacting said tissue with a suppressive amount of a suppressor of said metalloprotease inhibitor, wherein
 said metalloprotease inhibitor is TIMP-1 or TIMP-2, and   said suppressor is an antibody which specifically binds to and neutralizes said metalloprotease inhibitor.   
     
     
         20 . The method of  claim 19  where such contacting occurs in vivo, inside said subject.