Compositions and methods for treating and diagnosing cancer
The present invention relates to compositions and methods for characterizing, diagnosing and treating cancer. In particular, the present invention identifies LGR5 as a protein over-expressed in solid tumor stem cells. The present invention further identifies an interaction between RSPO1 and LGR5 as an alternative pathway for the activation of beta-catenin signaling. In certain embodiments, the present invention provides biomolecules that disrupt functional signaling via a LGR protein, including, in certain embodiments, molecules that inhibit the interaction between one or more RSPO proteins and one or more LGR proteins, such as LGR5. In certain embodiments, the present invention provides methods of treating cancer comprising disrupting functional LGR signaling and inhibiting growth of a solid tumor comprising solid tumor stem cells.
1. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that specifically binds to a human R-spondin (RSPO) protein, wherein the antibody:
(a) disrupts the binding of the RSPO protein to a human leucine-rich repeat-containing G protein-coupled receptor (LGR) protein; and/or
(b) disrupts RSPO activation of LGR signaling.
2. The method of claim 1 , wherein the RSPO protein is RSPO1.
3. The method of claim 1 , wherein the RSPO protein is RSPO2.
4. The method of claim 1 , wherein the RSPO protein is RSPO3.
5. The method of claim 1 , wherein the RSPO protein is RSPO4.
6. The method of claim 1 , wherein the LGR protein is LGR5.
7. The method of claim 1 , wherein the LGR protein is LGR4 or LGR6.
8. The method of claim 1 , wherein the antibody is a chimeric, humanized, or human antibody.
9. The method of claim 1 , wherein the antibody is an antibody fragment.
10. The method of claim 1 , wherein the antibody disrupts binding of the RSPO protein to a LGR protein.
11. The method of claim 1 , wherein the antibody disrupts RSPO activation of LGR signaling.
12. The method of claim 1 , wherein the cancer over-expresses LGR5.
13. The method of claim 1 , wherein the cancer is selected from the group consisting of colon cancer, ovarian cancer, breast cancer, lung cancer, and liver cancer.
14. The method of claim 1 , further comprising administering to the subject an effective amount of a second anticancer agent.
15. The method of claim 14 , wherein the second anticancer agent is a chemotherapeutic agent.
16. A method of inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that specifically binds to a RSPO protein, wherein the antibody:
(a) disrupts the binding of the RSPO protein to a human LGR protein; and/or
(b) disrupts RSPO activation of LGR signaling.
17. The method of claim 16 , wherein the RSPO protein is RSPO1.
18. The method of claim 16 , wherein the RSPO protein is RSPO2.
19. The method of claim 16 , wherein the RSPO protein is RSPO3.
20. The method of claim 16 , wherein the RSPO protein is RSPO4.
21. The method of claim 16 , wherein the LGR protein is LGR5.
22. The method of claim 16 , wherein the LGR protein is LGR4 or LGR6.
23. The method of claim 16 , wherein the antibody is a chimeric, humanized, or human antibody.
24. The method of claim 16 , wherein the antibody is an antibody fragment.
25. The method of claim 16 , wherein the antibody disrupts binding of the RSPO protein to a LGR protein.
26. The method of claim 16 , wherein the antibody disrupts RSPO activation of LGR signaling.
27. The method of claim 16 , wherein the tumor over-expresses LGR5.
28. The method of claim 16 , wherein the tumor is selected from the group consisting of a colon tumor, an ovarian tumor, abreast tumor, a lung tumor, and a liver tumor.
29. The method of claim 16 , further comprising administering to the subject an effective amount of a second anticancer agent.
30. The method of claim 29 , wherein the second anticancer agent is a chemotherapeutic agent.