Compositions and Methods for Therapy and Diagnosis of Cancer and Cancer Metastasis

Abstract

The present invention relates to methods which make possible to assess and/or prognose a cancer disease, the metastatic behaviour of a cancer disease and/or the occurrence of a relapse of cancer. In particular, the methods of the invention make possible to assess and/or prognose the occurrence of cancer metastasis, in particular distant metastasis. Preferably, the methods of the invention allow to discriminate malign from benign conditions.

1 . A method for diagnosing, monitoring and/or prognosing cancer, the metastatic behaviour of cancer and/or the presence of a relapse of cancer in a patient, which method comprises quantitatively and/or qualitatively determining the level of expression of TPTE in a biological sample isolated from said patient and quantitatively and/or qualitatively determining the level of expression of CXCR4 in a biological sample isolated from said patient. 
     
     
         2 . The method of  claim 1 , wherein a level of expression of TPTE and a level of expression of CXCR4 which is increased compared to the level of expression in a subject without cancer, without a risk for cancer, without metastasis of cancer, without a risk for metastasis of cancer, without a relapse of cancer, and/or without a risk for a relapse of cancer is indicative for cancer or for a potential for cancer, for a metastatic behaviour of cancer or for a potential for a metastatic behaviour of cancer and/or for a relapse of cancer or for a potential for a relapse of cancer. 
     
     
         3 . The method of  claim 1  or  2  wherein said quantitative and/or qualitative determination of the level of expression of TPTE comprises
 (i) detecting or determining the amount of a nucleic acid which is selected from the group consisting of:
 (a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, and 7, a part or derivative thereof, 
 (b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions, 
 (c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and 
 (d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c), and/or 
   (ii) detecting or determining the amount of a protein or peptide encoded by the nucleic acid under (i) or of a part or derivative thereof, and/or   (iii) detecting or determining the amount of an antibody specific for the protein or peptide or for the part or derivative under (ii), and/or   (iv) detecting or determining the amount of a T lymphocyte specific for the protein or peptide or for the part or derivative under (ii), optionally in a complex with a MHC molecule, in a biological sample isolated from a patient.   
     
     
         4 . The method of any one of  claims 1  to  3  wherein said quantitative and/or qualitative determination of the level of expression of CXCR4 comprises
 (i) detecting or determining the amount of a nucleic acid which is selected from the group consisting of:
 (a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 47, and 48, a part or derivative thereof, 
 (b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions, 
 (c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and 
 (d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c), and/or 
   (ii) detecting or determining the amount of a protein or peptide encoded by the nucleic acid under (i) or of a part or derivative thereof, and/or   (iii) detecting or determining the amount of an antibody specific for the protein or peptide or for the part or derivative under (ii), and/or   (iv) detecting or determining the amount of a T lymphocyte specific for the protein or peptide or for the part or derivative under (ii), optionally in a complex with a MHC molecule, in a biological sample isolated from a patient.   
     
     
         5 . The method of  claim 3  or  4 , wherein the nucleic acid under (i) in said quantitative and/or qualitative determination of the level of expression of TPTE comprises a nucleic acid sequence encoding a protein or peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, 12, 13, and 14, a part or derivative thereof and/or the protein or peptide under (ii) in said quantitative and/or qualitative determination of the level of expression of TPTE comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, 12, 13, and 14, a part or derivative thereof. 
     
     
         6 . The method of  claim 4  or  5 , wherein the nucleic acid under (i) in said quantitative and/or qualitative determination of the level of expression of CXCR4 comprises a nucleic acid sequence encoding a protein or peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, and 50, a part or derivative thereof and/or the protein or peptide under (ii) in said quantitative and/or qualitative determination of the level of expression of CXCR4 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, and 50, a part or derivative thereof. 
     
     
         7 . The method of any one of  claims 3  to  6 , wherein the detection or determination of the amount of said nucleic acid comprises
 (i) contacting the biological sample with an agent which binds specifically to the nucleic acid, and   (ii) detecting the formation of or determining the amount of a complex between the agent and the nucleic acid.   
     
     
         8 . The method of any one of  claims 3  to  6 , wherein the detection or determination of the amount of said protein or peptide or said part or derivative thereof comprises
 (i) contacting the biological sample with an agent which binds specifically to the protein or peptide or the part or derivative thereof, and   (ii) detecting the formation of or determining the amount of a complex between the agent and the protein or peptide or part or derivative thereof.   
     
     
         9 . The method of any one of  claims 3  to  6 , wherein the detection or determination of the amount of said antibody comprises
 (i) contacting the biological sample with an agent which binds specifically to the antibody, and   (ii) detecting the formation of or determining the amount of a complex between the agent and the antibody.   
     
     
         10 . The method of any one of  claims 3  to  6 , wherein the detection or determination of the amount of said T lymphocyte comprises
 (i) contacting the biological sample with an agent which binds specifically to the T lymphocyte, and   (ii) detecting the formation of or determining the amount of a complex between the agent and the T lymphocyte.   
     
     
         11 . The method of  claim 7 , wherein the agent which binds specifically to the nucleic acid is an oligonucleotide or polynucleotide, which hybridizes specifically to said nucleic acid. 
     
     
         12 . The method of  claim 8 , wherein the agent which binds specifically to the protein or peptide or the part or derivative thereof is an antibody binding specifically to said protein or peptide or to said part or derivative thereof. 
     
     
         13 . The method of  claim 9 , wherein the agent which binds specifically to the antibody is a protein or peptide binding specifically to said antibody. 
     
     
         14 . The method of  claim 10 , wherein the agent which binds specifically to the T lymphocyte is a cell presenting the complex between the protein or peptide or the part or derivative thereof for which the T lymphocyte is specific and an MHC molecule. 
     
     
         15 . The method of any one of  claims 1 - 14  wherein said monitoring comprises determining regression, course or onset of said cancer, said metastatic behaviour of cancer and/or said presence of a relapse of cancer. 
     
     
         16 . The method of  claim 15 , which comprises determining the level of expression in a first sample at a first point in time and in a further sample at a second point in time and a comparison of the two samples. 
     
     
         17 . The method of any one of  claims 1 - 16  wherein said patient has cancer, metastasis of cancer and/or a relapse of cancer or is suspected of or has a risk for falling ill with cancer, metastasis of cancer and/or a relapse of cancer. 
     
     
         18 . The method of any one of  claims 7 - 17 , wherein said agent is labeled in a detectable manner. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein said biological sample comprises body fluid and/or body tissue. 
     
     
         20 . A kit comprising means for quantitatively and/or qualitatively determining the level of expression of TPTE and means for quantitatively and/or qualitatively determining the level of expression of CXCR4 in a biological sample isolated from a patient. 
     
     
         21 . The kit of  claim 20  wherein said means for quantitatively and/or qualitatively determining the level of expression of TPTE are selected from the group consisting of
 (i) means for detecting or determining the amount of a nucleic acid which is selected from the group consisting of:
 (a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, and 7, a part or derivative thereof, 
 (b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions, 
 (c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and 
 (d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c), and/or 
   (ii) means for detecting or determining the amount of a protein or peptide encoded by the nucleic acid under (i) or of a part or derivative thereof, and/or   (iii) means for detecting or determining the amount of an antibody specific for the protein or peptide or the part or derivative under (ii), and/or   (iv) means for detecting or determining the amount of a T lymphocyte specific for the protein or peptide or the part or derivative under (ii), optionally in a complex with a MHC molecule, in a biological sample isolated from a patient.   
     
     
         22 . The kit of  claim 20  or  21  wherein said means for quantitatively and/or qualitatively determining the level of expression of CXCR4 are selected from the group consisting of
 (i) means for detecting or determining the amount of a nucleic acid which is selected from the group consisting of:
 (a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 47, and 48, a part or derivative thereof, 
 (b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions, 
 (c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and 
 (d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c), and/or 
   (ii) means for detecting or determining the amount of a protein or peptide encoded by the nucleic acid under (i) or of a part or derivative thereof, and/or   (iii) means for detecting or determining the amount of an antibody specific for the protein or peptide or the part or derivative under (ii), and/or   (iv) means for detecting or determining the amount of a T lymphocyte specific for the protein or peptide or the part or derivative under (ii), optionally in a complex with a MHC molecule, in a biological sample isolated from a patient.   
     
     
         23 . The kit of  claim 21  or  22 , wherein the nucleic acid under (i) in said quantitative and/or qualitative determination of the level of expression of TPTE comprises a nucleic acid sequence encoding a protein or peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, 12, 13, and 14, a part or derivative thereof and/or the protein or peptide under (ii) in said quantitative and/or qualitative determination of the level of expression of TPTE comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, 12, 13, and 14, a part or derivative thereof. 
     
     
         24 . The kit of  claim 22  or  23 , wherein the nucleic acid under (i) in said quantitative and/or qualitative determination of the level of expression of CXCR4 comprises a nucleic acid sequence encoding a protein or peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, and 50, a part or derivative thereof and/or the protein or peptide under (ii) in said quantitative and/or qualitative determination of the level of expression of CXCR4 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, and 50, a part or derivative thereof. 
     
     
         25 . The kit of any one of  claims 21  to  24 , wherein said means for detecting or determining the amount of said nucleic acid comprise an agent which binds specifically to the nucleic acid. 
     
     
         26 . The kit of any one of  claims 21  to  25 , wherein said means for detecting or determining the amount of said protein or peptide or part or derivative thereof comprise an agent which binds specifically to the protein or peptide or the part or derivative thereof. 
     
     
         27 . The kit of any one of  claims 21  to  26 , wherein said means for detecting or determining the amount of said antibody comprise an agent which binds specifically to the antibody. 
     
     
         28 . The kit of any one of  claims 21  to  27 , wherein said means for detecting or determining the amount of said T lymphocyte comprise an agent which binds specifically to the T lymphocyte. 
     
     
         29 . The kit of  claim 25 , wherein the agent which binds specifically to the nucleic acid is an oligonucleotide or polynucleotide, which hybridizes specifically to said nucleic acid. 
     
     
         30 . The kit of  claim 26 , wherein the agent which binds specifically to the protein or peptide or the part or derivative thereof is an antibody binding specifically to said protein or peptide or to said part or derivative thereof. 
     
     
         31 . The kit of  claim 27 , wherein the agent which binds specifically to the antibody is a protein or peptide binding specifically to said antibody. 
     
     
         32 . The kit of  claim 28 , wherein the agent which binds specifically to the T lymphocyte is a cell presenting the complex between the protein or peptide or the part or derivative thereof for which the T lymphocyte is specific and an MHC molecule. 
     
     
         33 . A pharmaceutical composition comprising (i) an agent which is effective in reducing or inhibiting expression or activity of TPTE and/or which binds to TPTE and has tumor destroying or tumor inhibiting activity, and (ii) an agent which is effective in reducing or inhibiting expression or activity of CXCR4 and/or which binds to CXCR4 and has tumor destroying or tumor inhibiting activity when administered to a patient. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the agent is an antisense nucleic acid which hybridizes selectively with the nucleic acid coding for TPTE and/or CXCR4. 
     
     
         35 . The pharmaceutical composition of  claim 33 , wherein the agent is a siRNA comprising a sense RNA strand and an antisense RNA strand, wherein the sense and antisense RNA strands form an RNA duplex, and wherein the sense RNA strand comprises a nucleotide sequence substantially identical to a target sequence of about 19 to about 25 contiguous nucleotides in TPTE mRNA and/or in CXCR4 mRNA. 
     
     
         36 . The pharmaceutical composition of  claim 33 , wherein the agent is an antibody which binds selectively to TPTE and/or CXCR4. 
     
     
         37 . A pharmaceutical composition comprising
 (I) one or more components selected from the group consisting of:
 (i) TPTE or a part thereof, 
 (ii) a nucleic acid which codes for TPTE or a part thereof, 
 (iii) an antibody which binds to TPTE or a part thereof, 
 (iv) an antisense nucleic acid which hybridizes specifically with a nucleic acid coding for TPTE, 
 (v) an siRNA directed against TPTE, 
 (vi) a host cell which expresses TPTE or a part thereof, and 
 (vii) isolated complexes between TPTE or a part thereof and an MHC molecule, and 
   (II) one or more components selected from the group consisting of:
 (i) CXCR4 or a part thereof, 
 (ii) a nucleic acid which codes for CXCR4 or a part thereof, 
 (iii) an antibody which binds to CXCR4 or a part thereof, 
 (iv) an antisense nucleic acid which hybridizes specifically with a nucleic acid coding for CXCR4, 
 (v) an siRNA directed against CXCR4, 
 (vi) a host cell which expresses CXCR4 or a part thereof, and 
 (vii) isolated complexes between CXCR4 or a part thereof and an MHC molecule. 
   
     
     
         38 . The pharmaceutical composition of  claim 36  or  37  wherein the antibody is coupled to a therapeutic substance. 
     
     
         39 . A method of treating cancer, metastasis of cancer or relapse of cancer comprising administering the pharmaceutical composition of any one of  claims 33 - 38 . 
     
     
         40 . The method of  claim 35 , wherein the cancer is a lung tumor, a breast tumor, a prostate tumor, a melanoma, a colon tumor, a gastric tumor, a pancreatic tumor, an ENT tumor, a renal cell carcinoma or a cervical carcinoma, a colon carcinoma or a mammary carcinoma.