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, the method comprising administering to the subject a therapeutically effective amount of a soluble receptor comprising an extracellular domain of a human leucine-rich repeat-containing G protein-coupled receptor (LGR) protein,
wherein the soluble receptor binds a human R-spondin (RSPO) protein, and
wherein the soluble receptor:
(a) disrupts RSPO activation of LGR signaling, and/or
(b) disrupts RSPO binding to LGR.
2. The method of claim 1 , wherein the LGR protein is LGR5.
3. The method of claim 1 , wherein the extracellular domain of the human LGR protein comprises amino acids 22-564 of human LGR5 (SEQ ID NO:1).
4. The method of claim 1 , wherein the soluble receptor binds a human RSPO protein selected from the group consisting of RSPO1, RSPO2, RSPO3, and RSPO4.
5. The method of claim 1 , wherein the method comprises administration of an additional anti-cancer agent.
6. The method of claim 1 , wherein the soluble receptor further comprises a non-LGR protein sequence.
7. The method of claim 6 , wherein the non-LGR protein sequence comprises a human Fc region.
8. The method of claim 1 , wherein the soluble receptor binds RSPO1.
9. The method of claim 1 , wherein the soluble receptor binds more than one human RSPO protein.
10. The method of claim 1 , wherein the soluble receptor disrupts RSPO activation of LGR signaling.
11. The method of claim 1 , wherein the soluble receptor RSPO binding to LGR.
12. A method of inhibiting growth of a tumor, the method comprising contacting the tumor or tumor cells with an effective amount of a soluble receptor comprising an extracellular domain of a human leucine-rich repeat-containing G protein-coupled receptor (LGR) protein,
wherein the soluble receptor binds a human R-spondin (RSPO) protein, and
wherein the soluble receptor disrupts RSPO activation of LGR signaling.
13. The method of claim 12 , wherein the LGR protein is LGR5.
14. The method of claim 12 , wherein the extracellular domain of the human LGR protein comprises amino acids 22-564 of human LGR5 (SEQ ID NO:1).
15. The method of claim 12 , wherein the soluble receptor further comprises a non-LGR protein sequence.
16. The method of claim 15 , wherein the non-LGR protein sequence comprises a human Fc region.
17. The method of claim 12 , wherein the soluble receptor binds a human RSPO protein selected from the group consisting of RSPO1, RSPO2, RSPO3, and RSPO4.
18. The method of claim 12 , wherein the soluble receptor binds RSPO1.
19. The method of claim 12 , wherein the soluble receptor binds more than one human RSPO protein.