Klotho protein and related compounds for the treatment and diagnosis of cancer

Abstract

Disclosed is the use of a klotho protein or related compounds for the diagnosis and treatment of cancer, alone or together with other active pharmaceutical ingredients such as chemotherapeutic agents or hormone-regulating agents.

1 - 31 . (canceled) 
     
     
         32 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising a klotho protein or a DNA encoding klotho protein. 
     
     
         33 . The method of  claim 32 , wherein said cancer is an IGF-1 dependent cancer. 
     
     
         34 . The method of  claim 32 , wherein said cancer is selected from the group consisting of colon cancer, prostate cancer, lung cancer, cervical cancer and ovarian cancer. 
     
     
         35 . The method of  claim 32 , wherein said cancer is breast cancer. 
     
     
         36 . The method of  claim 32 , wherein said cancer is pancreatic cancer. 
     
     
         37 . The method of  claim 32 , wherein said klotho protein comprises native klotho protein. 
     
     
         38 . The method of  claim 32 , wherein said klotho protein is a soluble protein. 
     
     
         39 . The method of  claim 32 , wherein said klotho protein is selected from the group consisting of:
 a) an isolated polypeptide including the amino acid sequence selected from the group of amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15;   b) an isolated polypeptide having a homology of at least 80% with a polypeptide including the amino acid sequence selected from the group of amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15;   c) an isolated polypeptide comprising an amino acid sequence wherein at least one amino acid of the amino acid sequence of a polypeptide comprising an amino acid sequence selected from amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15 is deleted, substituted or added; and   d) an isolated polypeptide comprising an amino acid sequence selected from the group of amino acid sequences represented by residues 31 to 982 of SEQ ID NO: 1, residues 34 to 1012 of SEQ ID NO: 1, residues 34 to 549 of SEQ ID NO: 2 and residues 36 to 1014 of SEQ ID NO: 3.   
     
     
         40 . The method of  claim 39 , wherein said homology is of at least 90% or more therewith. 
     
     
         41 . The method of  claim 32 , wherein said DNA encoding klotho protein is selected from the group consisting of:
 a) DNA encoding a polypeptide comprising an amino acid sequence selected from the amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15 or isolated polypeptides having a homology of at least 80% therewith or a DNA encoding a polypeptide comprising an amino acid sequence wherein at least one amino acid of the amino acid sequence of a polypeptide comprising an amino acid sequence selected from amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15 is deleted, substituted or added;   (b) DNA encoding a polypeptide comprising an amino acid sequence selected from the amino acid sequences represented by residues 31 to 982 of SEQ ID NO: 1, residues 34 to 1012 of SEQ ID NO: 1, residues 34 to 549 of SEQ ID NO: 2 and residues 36 to 1014 of SEQ ID NO: 3;   c) DNA comprising a DNA sequence selected from DNA sequences represented by SEQ ID NOS: 6, 7, 8, 9 and 10; and   d) DNA which hybridizes with a DNA described in (a), (b) or (c) under stringent conditions.   
     
     
         42 . The method of  claim 32 , wherein said DNA encoding klotho protein is provided inserted in a recombinant vector suitable for gene therapy. 
     
     
         43 . The method of  claim 32 , wherein said klotho protein or DNA encoding klotho protein is of a form selected from the group consisting of murine, human, bovine, canine or equine forms. 
     
     
         44 . A pharmaceutical composition comprising a klotho protein or DNA encoding klotho protein and a pharmaceutically acceptable carrier for use as a medicament for treating cancer. 
     
     
         45 . The composition of  claim 44 , wherein said cancer is an IGF-1 dependent cancer. 
     
     
         46 . The composition of  claim 45 , wherein said cancer is selected from the group consisting of colon cancer, prostate cancer, lung cancer, cervical cancer and ovarian cancer. 
     
     
         47 . The composition of  claim 44 , wherein said cancer is breast cancer. 
     
     
         48 . The composition of  claim 44 , wherein said cancer is pancreatic cancer. 
     
     
         49 . The composition of  claim 44 , wherein said klotho protein comprises native klotho protein. 
     
     
         50 . The composition of  claim 44 , wherein said klotho protein is a soluble protein. 
     
     
         51 . The composition of  claim 44 , wherein said klotho protein is selected from the group consisting of:
 a) an isolated polypeptide including the amino acid sequence selected from the group of amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15;   b) an isolated polypeptide having a homology of at least 80% with a polypeptide including the amino acid sequence selected from the group of amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15;   c) an isolated polypeptide comprising an amino acid sequence wherein at least one amino acid of the amino acid sequence of a polypeptide comprising an amino acid sequence selected from amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15 is deleted, substituted or added; and   d) an isolated polypeptide comprising an amino acid sequence selected from the group of amino acid sequences represented by residues 31 to 982 of SEQ ID NO: 1, residues 34 to 1012 of SEQ ID NO: 1, residues 34 to 549 of SEQ ID NO: 2 and residues 36 to 1014 of SEQ ID NO: 3.   
     
     
         52 . The composition of  claim 51 , wherein said homology is of at least 90% or more therewith. 
     
     
         53 . The composition of  claim 44 , wherein said DNA encoding klotho protein is selected from the group consisting of:
 a) DNA encoding a polypeptide comprising an amino acid sequence selected from the amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15 or isolated polypeptides having a homology of at least 80% therewith or a DNA encoding a polypeptide comprising an amino acid sequence wherein at least one amino acid of the amino acid sequence of a polypeptide comprising an amino acid sequence selected from amino acid sequences represented by SEQ ID NOS: 1, 2, 3, 4, 5, 11, 12, 13, 14 and 15 is deleted, substituted or added;   (b) DNA encoding a polypeptide comprising an amino acid sequence selected from the amino acid sequences represented by residues 31 to 982 of SEQ ID NO: 1, residues 34 to 1012 of SEQ ID NO: 1, residues 34 to 549 of SEQ ID NO: 2 and residues 36 to 1014 of SEQ ID NO: 3;   c) DNA comprising a DNA sequence selected from DNA sequences represented by SEQ ID NOS: 6, 7, 8, 9 and 10; and   d) DNA which hybridizes with a DNA described in (a), (b) or (c) under stringent conditions.   
     
     
         54 . The composition of  claim 44 , wherein said DNA encoding klotho protein is provided inserted in a recombinant vector suitable for gene therapy. 
     
     
         55 . The composition of  claim 44 , wherein said klotho protein or DNA encoding klotho protein is of a form selected from the group consisting of murine, human, bovine, canine or equine forms. 
     
     
         56 . A method for the diagnosis of cancer in a subject, the method comprising:
 measuring a level of klotho protein present in a test sample obtained from the subject; and   comparing said level of klotho protein in said test sample to that of a reference sample   wherein a reduced level of klotho protein in said test sample relative to that of said reference sample is indicative of the presence of cancer in the subject.   
     
     
         57 . A method of predicting the development of cancer in a benign breast disease patient, the method comprising:
 measuring a level of klotho protein in a test sample obtained from a benign breast lesion; and   comparing said level of klotho protein in said test sample to that of a reference sample comprising breast tissue from an area adjacent to said lesion   wherein a reduced level of klotho protein in said test sample relative to that of said reference sample is indicative of a relatively higher risk for developing breast cancer.