Thrombospondin-2 and uses thereof

• US 20050171016A1
• Filed: 11/24/2004
• Published: 08/04/2005
• Est. Priority Date: 03/31/1999
• Status: Abandoned Application

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Detmar, Michael, Streit, Michael
• Application Number:
  US10/997,699
• Publication Number:
  US 20050171016A1
• Time in Patent Office: Days
• US Class Current: 514/13.300
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]

Abstract

The invention features a method of treating a disorder characterized by unwanted angiogenesis and/or unwanted cellular proliferation, e.g., unwanted skin or prostate cell proliferation, by increasing a TSP-2 activity. The invention also features methods of identifying compounds which modulate, e.g., inhibit or promote, TSP-2 activity, and methods of evaluating if a subject is at risk for a disorder characterized by unwanted angiogenesis and/or unwanted cellular proliferation. The invention also features fragments and analogs of TSP-2 which can by used to treat such disorders.

Claims

1-55. -55. (canceled)

56. A method of treating a subject having an angiogenesis-dependent tumor, the method comprising:

identifying a subject having an angiogenesis-dependent tumor; and

administering to the subject a polypeptide comprising a fragment of SEQ ID NO;

2 (TSP-2) or a sequence at least 95% identical to SEQ ID NO;

2, wherein the fragment is capable of inhibiting endothelial cell migration, and comprises at least 10 amino acids of SEQ ID NO;

2 or the sequence at least 95% identical to SEQ ID NO;

2.

57. The method of claim 56, wherein the polypeptide comprises at least 10 contiguous amino acids of (a) a procollagen domain of TSP-2, or (b) a type I repeat of TSP-2.

58. The method of claim 56, wherein the fragment comprises the sequence of SEQ ID NO:

10 (WSPWAEW).

59. The method of claim 56, wherein the tumor is an epithelial tissue tumor, a skin tumor, a prostate tumor, a colon tumor, a breast tumor, a lung tumor, or a Kaposi'"'"'s sarcoma.

60. The method of claim 56, further comprising increasing TSP-1 activity, inhibiting VEGF activity, or administering a chemotherapeutic agent.

61. The method of claim 56, wherein the fragment is at least 50 amino acids in length.

62. The method of claim 57, wherein the fragment comprises one type I repeat.

63. The method of claim 57, wherein the fragment comprises between about 5 to 50 amino acids of a type I repeat.

64. The method of claim 56, wherein the fragment comprises at least one sequence selected from the group of:

amino acids 382-429 of SEQ ID NO;

2, amino acids 438-490 of SEQ ID NO;

2, and amino acids 495-547 of SEQ ID NO;

2.

65. The method of claim 56, wherein the fragment comprises SEQ ID NO:

11 (CSVTVG).

66. The method of claim 57, wherein the fragment comprises a procollagen domain or a fragment thereof.

67. The method of claim 56, wherein the fragment comprises two type I repeats.

68. The method of claim 56, wherein the fragment comprises three type I repeats.

69. The method of claim 56, wherein the fragment comprises an amino acid sequence encoded by nucleotides 294-1367 of SEQ ID NO:

1.

70. The method of claim 56, wherein the fragment comprises an amino acid sequence encoded by nucleotides 294-1883 of SEQ ID NO:

1.

71. The method of claim 56, wherein the fragment comprises an amino acid sequence encoded by nucleotides 1383-1883 of SEQ ID NO:

1.

72. The method of claim 56, wherein the polypeptide comprises TSP-2 (SEQ ID NO:

2).

73. The method of claim 72, wherein the polypeptide consists of TSP-2 (SEQ ID NO:

2).

74. A method of treating an angiogenesis-dependent tumor, the method comprising administering to the subject a fragment of TSP-2 comprising the sequence of SEQ ID NO:

10 (WSPWAEW).

75. A method of treating a subject having an angiogenesis-dependent tumor, the method comprising:

identifying a subject having an angiogenesis-dependent tumor; and

administering to the subject a cell genetically engineered to express TSP-2 (SEQ ID NO;

2) or a fragment thereof, capable of inhibiting endothelial cell migration, wherein the fragment comprises at least 10 amino acids of TSP-2.

76. The method of claim 75, wherein the TSP-2 or fragment thereof comprises at least 10 contiguous amino acids of (a) a procollagen domain of TSP-2, or (b) a type I repeat of TSP-2.

77. The method of claim 75, wherein the cell is selected from the group consisting of:

a fibroblast, a keratinocyte, an endothelial cell, a glial cell, a neural cell, a lymphocyte, a bone marrow cell, and a muscle cell.

78. The method of claim 75, wherein the tumor is selected from the group consisting of:

melanoma, a prostate tumor, a breast tumor, a colon tumor, and a lung tumor.

79. The method of claim 75, wherein the subject is a human.

80. The method of claim 76, wherein the cell is genetically engineered to express a fragment of TSP-2 capable of inhibiting endothelial cell migration, wherein the fragment comprises at least 10 contiguous amino acids of a type I repeat of TSP-2.