Use of rad18 inhibitors in the treatment of tumors

Abstract

The present invention relates to the use of an inhibitor of Rad18 expression or activity, in treating a tumor or in sensitizing a patient affected with a tumor, to a treatment with an antineoplastic agent that is a DNA damaging chemotherapeutic agent so to both reduce the self renewal of cancer stem cells and increase the DNA damage response thus boosting apoptotic cell death.

1 . A method for treating a tumor that is resistant to a treatment with a DNA damaging antineoplastic agent, in a patient, which method comprises administering an inhibitor of Rad18 expression or activity to the patient. 
     
     
         2 . The method according to  claim 1 , wherein the tumor is a tumor that comprises cancer stem cells, whereby the inhibitor kills said cancer stem cells, reduces self renewal of said cells and/or decreases the growth of said cells. 
     
     
         3 . The method according to  claim 1 , for reducing the risk of cancer relapse in the patient. 
     
     
         4 . The method according to  claim 1 , for sensitizing a patient affected with a tumor that is resistant to a treatment with a DNA damaging antineoplastic agent, wherein the tumor becomes sensitive to said antineoplastic agent. 
     
     
         5 . The method according to  claim 1 , wherein the antineoplastic agent is selected from the group consisting of (i) a platinum compound, preferably selected from the group consisting of cisplatin, carboplatin, oxaliplatin, arboplatin, nedaplatin, and satraplatin, (ii) an alkylating agent, such as methylmethane sulfonate, and (iii) a topoisomerase inhibitor, such as camptothecine. 
     
     
         6 . The method according to  claim 1 , wherein the inhibitor is to be administered within one day to one week before the patient is administered with said antineoplastic agent. 
     
     
         7 . The method according to  claim 1 , wherein the inhibitor is an inhibitor of Rad18 expression. 
     
     
         8 . The method according to  claim 7 , wherein the inhibitor of Rad18 expression is a nucleic acid that inhibits the expression of Rad18. 
     
     
         9 . The method according to  claim 7 , wherein the inhibitor of Rad18 expression is selected from the group consisting of a zinc-finger nuclease (ZFN), a transcription-activator like effector nuclease (TALEN), and a RNA-guided DNA endonuclease. 
     
     
         10 . The method according to  claim 1 , wherein the inhibitor is an inhibitor of Rad18 activity. 
     
     
         11 . The method according to  claim 10 , wherein the inhibitor of Rad18 activity is selected from the group consisting of a small molecule, an anti-Rad18 antibody, an inhibitor of the ubiquitine ligase activity of Rad18, and an inhibitor of Ubiquitine Specific Protease 7 (USP7). 
     
     
         12 . The method according to  claim 1 , wherein the tumor is of embryonic origin or generated by dedifferentiation of somatic cells. 
     
     
         13 . The method according to  claim 1 , wherein the tumor is selected from the group consisting of a glioblastoma, colorectal carcinoma, lung cancer, breast cancer, ovarian cancer and leukemia. 
     
     
         14 . A method for determining whether a tumor is resistant or, is expected to be resistant, to a therapy with a DNA damaging antineoplastic agent, which method comprises determining the expression level of Rad18 in the tumor, wherein a higher expression compared to a control is indicative of the presence of cancer stem cells which are resistant to a therapy with a DNA damaging antineoplastic agent. 
     
     
         15 . The method of  claim 14 , wherein the DNA damaging antineoplastic agent is selected from the group consisting of (i) a platinum compound, preferably selected from the group consisting of cisplatin, carboplatin, oxaliplatin, arboplatin, nedaplatin, and satraplatin, (ii) an alkylating agent, such as methylmethane sulfonate, and (iii) a topoisomerase inhibitor. 
     
     
         16 . A method for determining whether a patient treated for a tumor is at risk of a cancer relapse, which method comprises determining the expression level of Rad18 in the tumor or in a biological sample of the patient, wherein a higher expression compared to a control is indicative of the presence of cancer stem cells which are likely to develop and cause a cancer relapse. 
     
     
         17 . A method for monitoring efficacy of an anti-tumor treatment in a patient affected with a tumor which comprises cancer stem cells, which method comprises determining the expression level of Rad18 in the tumor or a biological sample of the patient, preferably a tumor sample, wherein a higher expression compared to a control is indicative of the presence of residual cancer stem cells. 
     
     
         18 . The method according to  claim 8 , wherein the inhibitor is selected from the group consisting of small interfering RNA (siRNA), small hairpin RNA (shRNA), micro RNA (miRNA), an aptamer, a ribozyme, and an antisense oligonucleotide. 
     
     
         19 . The method according to  claim 2 , for reducing the risk of cancer relapse in the patient. 
     
     
         20 . The method according to  claim 2 , for sensitizing a patient affected with a tumor that is resistant to a treatment with a DNA damaging antineoplastic agent, wherein the tumor becomes sensitive to said antineoplastic agent.