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 inhibiting beta-catenin signaling in a tumor cell, the method comprising contacting the tumor cell with an effective amount of a monoclonal antibody that inhibits binding of a human R-spondin (RSPO) protein to a human leucine-rich repeat-containing G protein-coupled receptor (LGR) protein.
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 antibody, a humanized antibody, a human antibody, or an antibody fragment.
9. The method of claim 1 , wherein the antibody specifically binds to a RSPO protein.
10. The method of claim 1 , wherein the tumor cell is a lung tumor, gastrointestinal tumor, pancreatic tumor, glioblastoma, cervical tumor, ovarian tumor, liver tumor, bladder tumor, kidney tumor, breast tumor, colon tumor, colorectal tumor, prostate tumor, and various types of head and neck tumors.
11. The method of claim 1 , further comprising administering an effective amount of a second anticancer agent.
12. The method of claim 11 , wherein the second anticancer agent is a chemotherapeutic agent.
13. A method of inhibiting beta-catenin signaling in a tumor cell, the method comprising contacting the cell with an effective amount of a monoclonal antibody that inhibits RSPO activation of LGR signaling.
14. The method of claim 13 , wherein the RSPO protein is RSPO1.
15. The method of claim 13 , wherein the RSPO protein is RSPO2.
16. The method of claim 13 , wherein the RSPO protein is RSPO3.
17. The method of claim 13 , wherein the RSPO protein is RSPO4.
18. The method of claim 13 , wherein the LGR protein is LGR5.
19. The method of claim 13 , wherein the LGR protein is LGR4 or LGR6.
20. The method of claim 13 , wherein the antibody is a chimeric antibody, a humanized antibody, a human antibody, or an antibody fragment.
21. The method of claim 13 , wherein the antibody specifically binds to a RSPO protein.
22. The method of claim 13 , wherein the tumor cell is a lung tumor, gastrointestinal tumor, pancreatic tumor, glioblastoma, cervical tumor, ovarian tumor, liver tumor, bladder tumor, kidney tumor, breast tumor, colon tumor, colorectal tumor, prostate tumor, and various types of head and neck tumors.
23. The method of claim 13 , further comprising administering an effective amount of a second anticancer agent.
24. The method of claim 23 , wherein the second anticancer agent is a chemotherapeutic agent.