Compositions and methods for treating malignancies
Provided by the invention are methods for identifying therapeutic agents for treating multiple myeloma or another hematological malignancy, as well as methods for determining the prognosis of a patient with multiple myeloma or another hematological malignancy. The methods are based in part on the inventors' discovery that an extracellular form of cyclophilin A binds to CD147 expressed on multiple myeloma cells.
1. A method for identifying a therapeutic agent for treating multiple myeloma (MM), the method comprising:
(a) providing a first polypeptide comprising a CD147 polypeptide and a second polypeptide comprising an extracellular cyclophilin A (eCyPA) polypeptide sequence under conditions that allow for binding of the CD147 polypeptide and the eCyPA sequence;
(b) contacting the complex with a test agent;
(c) determining whether the test agent disrupts binding of the first and second polypeptide,
wherein disruption of the binding of the first polypeptide and second polypeptide by the test agent indicates the test agent is a putative therapeutic agent for treating MM;
(d) contacting the putative therapeutic agent with a multiple myeloma (MM) cell population expressing CD147; and
(e) determining whether the putative therapeutic agent inhibits migration of MM cells from the MM cell population into bone marrow,
wherein inhibition of MM cell migration indicates the test agent is a therapeutic agent for treating MM.
2. The method of claim 1 , wherein the CD147 polypeptide is provided in a cell expressing a CD147 polypeptide sequence.
3. The method of claim 2 , wherein the cell expressing a CD147 polypeptide sequence is provided in vitro.
4. The method of claim 2 , wherein the cell expressing a CD147 polypeptide sequence is provided in vivo.
5. The method of claim 2 , wherein the cell expressing a CD147 polypeptide sequence is a human cell.
6. The method of claim 2 , wherein the cell expressing a CD147 polypeptide sequence is a lymphocyte, optionally wherein the lymphocyte is a B cell.
7. The method of claim 2 , wherein the cell expressing a CD147 polypeptide sequence is a multiple myeloma cell.
8. The method of claim 1 , wherein the amino acid sequence of the eCyPA polypeptide is set forth in SEQ ID NO:1.
9. The method of claim 1 , wherein the amino acid sequence of the CD147 polypeptide is set forth in SEQ ID NO:2.
10. The method of claim 1 , wherein the test agent is a nucleic acid, a polypeptide, a small molecule, or combinations thereof.
11. The method of claim 10 , wherein the test agent is a nucleic acid, and wherein the nucleic acid is an inhibitory nucleic acid.
12. The method of claim 11 , wherein the inhibitory nucleic acid is a triplex forming oligonucleotide, an aptamer, a ribozyme, an antisense RNA, a short interfering RNA (siRNA), or a micro-RNA (miRNA).
13. The method of claim 10 , wherein the test agent is a polypeptide, and wherein the polypeptide is an antibody or an antigen-binding derivative thereof.
14. The method of claim 13 , wherein antibody or an antigen-binding derivative thereof specifically binds to CyPA.
15. The method of claim 14 , wherein the antibody or antigen-binding derivative thereof is humanized.
16. The method of claim 1 , wherein disruption of the binding of the first polypeptide and second polypeptide by the test agent indicates the test agent is a putative therapeutic agent for treating chronic lymphocytic leukemia (CLL) or lymphoplasmacytic lymphoma (LPL).