Methods and monitoring of treatment with a WNT pathway inhibitor
Methods for treating diseases such as cancer comprising administering a Wnt pathway inhibitor, either alone or in combination with other anti-cancer agents, and monitoring for skeletal-related side effects and/or toxicity.
1. A method of treating cancer in a subject in need thereof, comprising:
(a) administering to the subject a therapeutically effective amount of a soluble receptor comprising a Fri domain of a human FZD8 protein; and
(b) determining the level of a bone resorption biomarker in a sample from the subject.
2. The method of claim 1 , wherein the Fri domain of a human FZD8 protein is selected from the group consisting of SEQ II) NO:20, SEQ ID NO: 30, or SEQ ID NO:33.
3. The method of claim 1 , wherein the soluble receptor further comprises a non-FZD8 polypeptide, and wherein the Fri domain of a human FZD8 protein is directly linked to the non-FZD8 polypeptide or is linked to the non-FZD8 polypeptide by a linker.
4. The method of claim 3 , wherein the non-FZD8 polypeptide comprises a human Fe region.
5. The method of claim 4 , wherein the human Fe region consists of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, or SEQ ID NO:38.
6. The method of claim 1 , wherein the soluble receptor comprises
(a) a first polypeptide consisting essentially of SEQ ID NO:20, SEQ ID NO:30, or SEQ ID NO:33; and
(b) a second polypeptide consisting essentially of SEQ II) NO:34, SR) II) NO:35, SEQ ID NO:36, SEQ ID NO:37, or SEQ ID NO:38;
wherein the first polypeptide is directly linked to the second polypeptide or the first polypeptide is connected to the second polypeptide by a linker.
7. The method of claim 1 , wherein the soluble receptor comprises the amino acid sequence of SEQ ID NO: 45.
8. The method of claim 1 , wherein the soluble receptor is 54F28.
9. The method of claim 1 , wherein the bone resorption biomarker is selected from the group consisting of: urinary hydroxyproline, urinary total pyridinoline (PYD), urinary free deoxypryidinoline (DPD), urinary collagen type 1 cross-linked N-telopeptide (NTX), urinary or serum collagen type 1 cross-linked C-telopeptide (CTX), bone sialoprotein (BSP), and tartrate-resistant acid phosphatase 5b and β-CTX.
10. The method of claim 9 , wherein the bone resorption biomarker is β-CTX.
11. A method for reducing a skeletal-related side effect and/or toxicity in a subject receiving treatment with a soluble receptor comprising a Fri domain of a human FZD8 protein, comprising administering to the subject a therapeutically effective amount of an anti-resorptive medication.
12. The method of claim 11 , wherein the soluble receptor comprising a Fri domain of human FZD8 protein comprises
(a) a first polypeptide consisting essentially of SEQ ID NO:20, SEQ. ID NO:30, or SEQ ID NO:33; and
(b) a second polypeptide consisting essentially of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, or SEQ ID NO:38;
wherein the first polypeptide is directly linked to the second polypeptide or the first polypeptide is connected to the second polypeptide by a linker.
13. The method of claim 11 , wherein the soluble receptor comprises the amino acid sequence of SEQ ID NO: 45.
14. The method of claim 11 , wherein the soluble receptor is 54F28.
15. The method of claim 11 , wherein the anti-resorptive medication is a bisphosphonate or denosumab.
16. A method of preventing or attenuating the development of a skeletal-related side effect and/or toxicity in a subject receiving treatment with a soluble receptor comprising a Fri domain of a human FZD8 protein, comprising administering to the subject a therapeutically effective amount of an anti-resorptive medication.
17. The method of claim 16 , wherein the soluble receptor comprising a Fri domain of human FZD8 protein comprises
(a) a first polypeptide consisting essentially of SEQ ID NO:20, SEQ ID NO:30, or SEQ ID NO:33; and
(b) a second polypeptide consisting essentially of SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ NO:37, or SEQ II) NO:38;
wherein the first polypeptide is directly linked to the second polypeptide or the first polypeptide is connected to the second polypeptide by a linker.
18. The method of claim 16 , wherein the soluble receptor comprises the amino acid sequence of SEQ ID NO: 45.
19. The method of claim 16 , wherein the soluble receptor is 54F28.
20. The method of claim 16 , wherein the anti-resorptive medication is a bisphosphonate or denosumab.