Use of vegfr1 as a biomarker

Abstract

The present invention is related to the use of VEGFR1 or of a nucleic acid coding for VEGFR1 as a biomarker in a method for the treatment of a subject, wherein the method for the treatment comprises administering to the subject a PKN3 inhibitor.

We claim: 
     
         1 . A method for deciding whether a subject having undergone a first method of treatment, wherein the first method of treatment comprises administering to the subject a PKN3 inhibitor, shall be subject to a second method of treatment, wherein the second method of treatment comprises administering to the subject a PKN3 inhibitor, comprising:
 determining the level of a VEGFR1 or of a nucleic acid coding for a VEGFR1 in a sample from the subject prior to a first method of treatment,   determining the level of a VEGFR1 or of a nucleic acid coding for a VEGFR1 in a sample from the subject after a first period of time after the first method of treatment, and   optionally determining the level of a VEGFR1 or of a nucleic acid coding for a VEGFR1 in a sample from the subject after a second period of time after the first method of treatment,   wherein if the level of a VEGFR1 or of a nucleic acid coding for a VEGFR1 in a sample from the subject after the first or second period of time after the first method of treatment is increased compared to the level of a VEGFR1 or of a nucleic acid coding for a VEGFR1 in a sample from the subject prior to a first method of treatment, the subject is to be subjected to the second method of treatment.   
     
     
         2 . The method according to  claim 1 , wherein the increase is 100% or more, 80% or more, 60% or more or 40% or more. 
     
     
         3 . The method according to  claim 1 , wherein the subject is suffering from a disease or is at risk of suffering from a disease and wherein the method of treatment is a method of treatment for the disease. 
     
     
         4 . The method according to  claim 1 , wherein first period of time after the first method of treatment is about 24 hours or 48 hours after the last administration of the PKN3 inhibitor being part of the first method of treatment. 
     
     
         5 . The method according to  claim 1 , wherein the second period of time after the first method of treatment starts about 1 or two months after the first period of time after the first method of treatment. 
     
     
         6 . The method according to  claim 1 , wherein the first method of treatment is the same as the second method of treatment, or wherein the first method of treatment is different from the second method of treatment. 
     
     
         7 . The method according to  claim 1 , wherein the PKN3 inhibitor selected from the group consisting of an siRNA directed against an mRNA coding for PKN3, an antisense oligonucleotide directed against an mRNA coding for PKN3, a ribozyme directed against an mRNA coding for PKN3, an shRNA directed against an mRNA coding for PKN3, an miRNA or antagomir directed against an mRNA coding for PKN3, an aptamer directed against PKN3, a spiegelmer directed against PKN3, an antibody directed against PKN3, an anticalin directed against PKN3, and a small molecule. 
     
     
         8 . The method according to  claim 7 , wherein the PKN3 inhibitor is an siRNA wherein the siRNA is as follows:
   5′ 5 u 8 u 7 c 6 g 8 a 6 g 5 c 7 u 7 a 6 g 5 c 5 3′
     3′  a 6 c 6 g 8 u 7 c 5 u 7 a 8 g 6 g 5 u 7 a 8 a  5′
   
       with unmodified ribonuclotides being as indicated and modified ribonucleotides being represented as follows:
 5: 2′-O-Methyl-u, 
 6: 2′-O-Methyl-a, 
 7: 2′-O-Methyl-c, 
 8: 2′-O-Methyl-g. 
 
     
     
         9 . The method according to  claim 1 , wherein the VEGFR1 is VEGFR1, VEGFR1 variant 2, VEGFR1 variant 1, VEGFR1 variant 3, VEGFR1 variant 4, soluble VEGFR1, or soluble VEGFR1 variant 2 or is a nucleic acid encoding VEGFR1, VEGFR1 variant 2, VEGFR1 variant 1, VEGFR1 variant 3, VEGFR1 variant 4, soluble VEGFR1, or soluble VEGFR1 variant 2. 
     
     
         10 . A method for deciding whether a subject shall undergo a method of treatment, whereby the method of treatment comprises the administration of a PKN3 inhibitor, comprising determining the level of a VEGFR1 or of a nucleic acid coding for a VEGFR1, or determining the expression level of a VEGFR1 or of a nucleic acid coding for a VEGFR1, wherein if the expression level of a VEGFR1 or of a nucleic acid coding for a VEGFR1, expressed as titre of VEGF1 in blood or plasma of the subject, is equal to or greater than 200 pg/ml, the patient is amenable to the method of treatment comprising administration of a PKN3 inhibitor. 
     
     
         11 . The method according to  claim 10 , wherein if the expression level of VEGFR1 or of a nucleic acid coding for VEGFR1, expressed as titre of VEGF1 in blood or plasma of the subject, is equal to or greater than 400 pg/ml, preferably equal to or greater than 600 pg/ml, more preferably equal to or greater than 800 pg/ml, the patient is amenable to the method of treatment comprising administration of a PKN3 inhibitor. 
     
     
         12 . The method according to  claim 10 , wherein the disease is selected from the group consisting of tumor diseases, cancer diseases and pre-eclampsia. 
     
     
         13 . The method according to  claim 10 , wherein the PKN3 inhibitor selected from the group consisting of an siRNA directed against an mRNA coding for PKN3, an antisense oligonucleotide directed against an mRNA coding for PKN3, a ribozyme directed against an mRNA coding for PKN3, an shRNA directed against an mRNA coding for PKN3, an miRNA or antagomir directed against an mRNA coding for PKN3, an aptamer directed against PKN3, a spiegelmer directed against PKN3, an antibody directed against PKN3, an anticalin directed against PKN3, and a small molecule. 
     
     
         14 . The method according to  claim 13 , wherein the PKN3 inhibitor is an siRNA wherein the siRNA is as follows:
   5′ 5 u 8 u 7 c 6 g 8 a 6 g 5 c 7 u 7 a 6 g 5 c 5 3′
     3′  a 6 c 6 g 8 u 7 c 5 u 7 a 8 g 6 g 5 u 7 a 8 a  5′
   
       with unmodified ribonuclotides being as indicated and modified ribonucleotides being represented as follows:
 5: 2′-O-Methyl-u, 
 6: 2′-O-Methyl-a, 
 7: 2′-O-Methyl-c, 
 8: 2′-O-Methyl-g. 
 
     
     
         15 . The method according to  claim 10 , wherein the PKN3 inhibitor selected from the group consisting of an siRNA directed against an mRNA coding for PKN3, an antisense oligonucleotide directed against an mRNA coding for PKN3, a ribozyme directed against an mRNA coding for PKN3, an shRNA directed against an mRNA coding for PKN3, an miRNA or antagomir directed against an mRNA coding for PKN3, an aptamer directed against PKN3, a spiegelmer directed against PKN3, an antibody directed against PKN3, an anticalin directed against PKN3, and a small molecule. 
     
     
         16 . The method according to  claim 15 , wherein the PKN3 inhibitor is an siRNA wherein the siRNA is as follows:
   5′ 5 u 8 u 7 c 6 g 8 a 6 g 5 c 7 u 7 a 6 g 5 c 5 3′
     3′  a 6 c 6 g 8 u 7 c 5 u 7 a 8 g 6 g 5 u 7 a 8 a  5′
   
       with unmodified ribonuclotides being as indicated and modified ribonucleotides being represented as follows:
 5: 2′-O-Methyl-u, 
 6: 2′-O-Methyl-a, 
 7: 2′-O-Methyl-c, 
 8: 2′-O-Methyl-g. 
 
     
     
         17 . The method according to  claim 10 , wherein the VEGFR1 is VEGFR1, VEGFR1 variant 2, VEGFR1 variant 1, VEGFR1 variant 3, VEGFR1 variant 4, soluble VEGFR1, or soluble VEGFR1 variant 2 or is a nucleic acid encoding VEGFR1, VEGFR1 variant 2, VEGFR1 variant 1, VEGFR1 variant 3, VEGFR1 variant 4, soluble VEGFR1, or soluble VEGFR1 variant 2. 
     
     
         18 . A method for the treatment of a subject suffering from or being at risk of suffering from a disease associated with the expression level of a VEGFR1 or of a nucleic acid coding for a VEGFR1, said expression level being expressed as titre of a VEGF1 in blood or plasma of the subject that is equal to or greater than 200 pg/ml, comprising measuring the expression level of a VEGFR1 or of a nucleic acid coding for a VEGFR1 in said subject and administering a PKN3 inhibitor to said subject having an expression level that is equal to or greater than 200 pg/ml. 
     
     
         19 . The method according to  claim 18 , wherein the expression level of a VEGFR1 or of a nucleic acid coding for a VEGFR1, expressed as titre of a VEGF1 in blood or plasma of the subject, is equal to or greater than 400 pg/ml, equal to or greater than 600 pg/ml or equal to or greater than 800 pg/ml. 
     
     
         20 . The method according to  claim 18 , wherein the VEGFR1 is VEGFR1, VEGFR1 variant 2, VEGFR1 variant 1, VEGFR1 variant 3, VEGFR1 variant 4, soluble VEGFR1, or soluble VEGFR1 variant 2 or is a nucleic acid encoding VEGFR1, VEGFR1 variant 2, VEGFR1 variant 1, VEGFR1 variant 3, VEGFR1 variant 4, soluble VEGFR1, or soluble VEGFR1 variant 2.