Therapeutic agents for the treatment of diseases associated with undesired cell proliferation

Abstract

The invention is based on observing that LIF is capable of activating the self-renewal of tumor stem cells in cancer, in particular gliomas, which indicates that the inhibition of LIF, and generally of IL-6 type cytokines, can be used in therapeutic compositions for the treatment of diseases associated with unwanted proliferation. The invention also relates to a method for the identification of compounds capable of blocking/inhibiting the proliferation of stem cells, and to an in vitro method for the diagnosis of diseases associated with unwanted cell proliferation in a subject or for determining the predisposition of a subject to suffer said disease associated with unwanted cell proliferation, or for prognosis of average life expectancy of subjects suffering from said tumors.

1 . An inhibitory agent of the expression and/or the activity of an IL-6 type cytokine for the treatment of diseases associated with unwanted cell proliferation. 
     
     
         2 . The inhibitory agent according to  claim 1 , wherein said agent acts through the inhibition of the self-regeneration of tumor stem cells. 
     
     
         3 . The agent according to  claim 2 , wherein the inhibitory agent is selected from the group consisting of siRNAs, antisense oligonucleotides, specific ribozymes, antibodies, polypeptides and inhibitors of cytokine receptor binding. 
     
     
         4 . The agent according to  claim 3 , wherein the antibodies are inhibitory antibodies specific to said IL-6 type cytokine or antibodies blocking IL-6 type cytokine receptors. 
     
     
         5 . The agent according to  claim 1 , wherein said IL-6 type cytokine is selected from LIF, IL-6, IL-11, oncostatin M, cardiotrophin-1, CNTF and CLC. 
     
     
         6 . The agent according to  claim 1 , wherein the IL-6 type cytokine is LIF. 
     
     
         7 . The agent according to  claim 1 , wherein said disease presenting unwanted cell proliferation is cancer. 
     
     
         8 . The agent according to  claim 7 , wherein the cancer is characterized by presenting high levels of IL-6 type cytokine. 
     
     
         9 . The agent according to  claim 7 , wherein said cancer is caused by a high activity of the JAK-STAT signaling pathway. 
     
     
         10 . The agent according to  claim 7 , wherein said cancer is one of the following: glioma, pre-B cell acute lymphoblastic leukemia, acute myeloid leukemia, colorectal carcinoma, bladder cancer, breast ductal cancer or breast carcinoma. 
     
     
         11 . The agent according to  claim 10 , wherein said glioma is grade IV glioma. 
     
     
         12 . A pharmaceutical composition comprising a therapeutically effective amount of an agent according to  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         13 . In vitro method for the identification of compounds capable of blocking/inhibiting the cell proliferation of tumor cells induced by an IL-6 type cytokine or a functionally equivalent variant thereof, comprising the steps of:
 (i) contacting a cell expressing the receptor for an IL-6 type cytokine with an IL-6 type cytokine and a candidate compound, and   (ii) identifying those compounds blocking the cell proliferation of said cell.   
     
     
         14 . The method according to  claim 13 , wherein the cell expressing the receptor for an IL-6 type cytokine is a glioma cell, preferably a glioma initiating cell (GIC). 
     
     
         15 . The method according to  claim 13 , wherein said IL-6 type cytokine is selected from LIF, IL-6, IL-11, oncostatin M, cardiotrophin-1, CNTF and CLC. 
     
     
         16 . The method according to  claim 15 , wherein the IL-6 type cytokine is LIF. 
     
     
         17 - 54 . (canceled) 
     
     
         55 . An in vitro method for measuring the levels of said cytokine in a patient suffering from a disease associated with unwanted cell proliferation comprising:
 (a) quantifying the expression levels of the IL-6 type cytokine in said patient, and   (b) comparing said expression levels with control levels of patients suffering from the same disease, wherein if the expression levels of an IL-6 type cytokine in said patient are significantly greater than the control values.   
     
     
         56 . The method according to  claim 55 , wherein said IL-6 type cytokine is selected from LIF, IL-6, IL-11, oncostatin M, cardiotrophin-1, CNTF and CLC. 
     
     
         57 . The method according to  claim 55 , wherein the IL-6 type cytokine is LIF. 
     
     
         58 . The method according to  claim 55 , wherein said disease associated with unwanted cell proliferation is cancer.