Use of biomolecular targets in the treatment and visualization of brain tumors
The present invention relates to the use of proteins that are differentially expressed in primary brain tumor tissues, as compared to normal brain tissues, as biomolecular targets for brain tumor treatment therapies. Specifically, the present invention relates to the use of therapeutic and imaging agents, which specifically bind to one or more of the identified brain tumor protein targets. The present invention also provides compounds and pharmaceutically acceptable compositions for administration in the methods of the invention. Nucleic acid probes specific for the spliced mRNA encoding these variants and affinity reagents specific for the novel proteins are also provided.
1 . A method for the diagnosis or staging of a brain tumor, the method comprising:
determining the upregulation of expression of DDR1 mRNA or polypeptide in said brain tumor.
2 . The method according to claim 1 , wherein said astrocytoma is a grade II, grade III astrocytoma and grade IV astrocytoma.
3 . The method according to claim 1 , wherein said DDR1 is selected from the group consisting of the DDR1a isotype, DDR1b isotype, DDR1e isotype, soluble DDR1, and glioma specific isoforms.
4 . A method to treat a brain tumor, the method comprising:
administering a therapeutic amount of a compound that binds to, or inhibits, DDR1.
5 . The method according to claim 4 , wherein said compound inhibits invasion, ligand binding, angiogenesis, survival, MMP production, ectodomain cleavage, biologic activity, and cell adhesion of astrocytoma cells.
6 . The method of claim 4 wherein said compound is administered by intrathecal administration.
7 . The method of claim 6 , wherein said compound is formulated for retention and stability in the brain.
8 . The method of claim 6 wherein said compound is administered by intravascular administration.
9 . The method of claim 6 , wherein said compound is a specific binding partner for DDR1.
10 . The method according to claim 9 , wherein said specific binding partner is conjugated to a cytotoxic moiety.
11 . The method according to claim 9 , wherein said binding partner is internalized by said astrocytoma cell.
12 . The method according to claim 9 , wherein said specific binding partner is an antibody.
13 . The method according to claim 12 , wherein said antibody binds to an epitope selected from the group consisting of the discoidin domain; the F5/8 type C domain; the RFRR protease recognition site; amino acid sequence 380-416, and the gly-pro rich domains.
14 . The method according to claim 9 , wherein said specific binding member is a collagen fragment that binds to DDR1.
15 . The method according to claim 9 , wherein said specific binding member is a soluble fragment of DDR1 that forms a homotypic dimmer with membrane bound DDR1.
16 . The method according to claim 9 , wherein said specific binding member is a fibronectin fragment that binds to DDR1.
17 . A method of screening candidate agents for effectiveness against an astrocytoma, the method comprising:
combining a candidate biologically active agent with a DDR1 polypeptide; or a cell comprising a nucleic acid encoding and expressing a DDR1 polypeptide; and
determining the effect of said agent on DDR1 activity, wherein agents that modulate polypeptide activity provide for molecular and cellular changes in brain tumor cells.
18 . The method according to claim 17 , wherein said biologically active agent modulates activity of said polypeptide.
19 . The method according to claim 17 , wherein said activity is DDR1 mediated modulation of matrix metalloprotease activity.
20 . The method according to claim 17 , wherein said activity is invasion of extracellular matrix.