METHODS OF TREATING CANCER

• US 20130263297A1
• Filed: 05/07/2013
• Published: 10/03/2013
• Est. Priority Date: 11/10/2010
• Status: Abandoned Application

• Current Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Original Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Inventors: Chung, Leland W.K., Zhau, Haiyen E., Wang, Ruoxiang, Chu, Gina C.Y.
• Application Number:
  US13/889,135
• Publication Number:
  US 20130263297A1
• Time in Patent Office: Days
• US Class Current: 800/10
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241

Abstract

The present invention relates to metastases. More specifically, the invention relates to compositions and methods for the inhibition of metastases of cancer cells, such as prostate cancer cells, to bones and soft tissue. The present invention also relates to the treatment of cancer, including but not limited to prostate cancer. Also provided are animal models for studying cancer metastasis; particularly, prostate cancer metastasis. Further provided are compositions, processes and systems to prognosticate cancer.

Claims

1. A method for treating cancer in a mammalian subject in need thereof, comprising:

providing an agent capable of inhibiting RANK and/or RANKL, and an agent capable of inhibiting HGF-c-Met/VEGFR2/neuropilin-1-mediated signaling; and

administering the agent capable of inhibiting RANK and/or RANKL and the agent capable of inhibiting HGF-c-Met/VEGFR2/neuropilin-1-mediated signaling to the mammalian subject to treat cancer.

2. The method of claim 1, wherein the agent capable of inhibiting RANK and/or RANKL is provided in a first composition and the agent capable of inhibiting HGF-c-Met/VEGFR2/neuropilin-1-mediated signaling is provided in a second composition.

3. The method of claim 1, wherein the agent capable of inhibiting RANK and/or RANKL and the agent capable of inhibiting HGF-c-Met/VEGFR2/neuropilin-1-mediated signaling are provided in one composition.

4. The method of claim 1, wherein the agent capable of inhibiting RANK and/or RANKL is denosumab, RANK-Fc, OPG-Fc, shRNA, or siRNA.

6. The method of claim 1, wherein the agent capable of inhibiting RANK and/or RANKL is denosumab.

7. The method of claim 1, wherein the agent capable of inhibiting HGF-c-Met/VEGFR2/neuropilin-1-mediated signaling is denosumab, RANK-Fc, OPG-Fc, shRNA, siRNA, crizotinib, or VEGFR2 kinase inhibitor III (CAS 204005-46-9).

9. The method of claim 1, wherein the cancer is prostate, kidney, breast, bladder, lung, breast, ovarian, pancreatic, thyroid, liver, gastric, colon or melanoma.

10. The method of claim 1, wherein the cancer is prostate cancer.

11. The method of claim 1, wherein the inhibiting HGF-c-Met/VEGFR2/neuropilin-1-mediated signaling comprises inhibiting activation of c-Met, VEGFR2, neuropilin-1, Src-kinase, Stat3, Mcl-1, NF-kB or combinations thereof.

5. (canceled)

8. (canceled)

12. A method of preventing, reducing the likelihood of and/or inhibiting metastases of cancer cells, comprising:

providing a composition comprising an agent capable of inhibiting epithelial-to-mesenchymal transition (EMT) of cancer cells; and

administering a quantity of the composition to the a mammalian subject in need thereof to prevent, reduce the likelihood of and/or inhibit metastases of cancer cells.

13. The method of claim 12, wherein the agent capable of inhibiting EMT is osteoprotegerin (OPG) and binds to RANKL to inhibit the formation of osteoclasts, thereby preventing, reducing the likelihood and/or inhibiting metastases of the cancer cells.

14. The method of claim 12, wherein the agent capable of inhibiting EMT is denosumab, RANK-Fc, OPG-Fc, siRNA, shRNA, crizotinib, or VEGFR2 kinase inhibitor III (CAS 204005-46-9) or combinations thereof.

16. The method of claim 12, wherein the cancer cells are prostate, kidney, breast, bladder, lung, ovarian, pancreatic, thyroid, liver, gastric, colon or melanoma cancer cells.

17. The method according to claim 12, wherein the cancer cells are prostate cancer cells.

15. (canceled)

18. A method of inhibiting a process of RANKL-mediated awakening of cancer dormancy, comprising:

providing a composition comprising an agent capable of inhibiting epithelial-to-mesenchymal transition (EMT) of cancer cells; and

administering a quantity of the composition to the a mammalian subject in need thereof to inhibiting the process of RANKL-mediated awakening of cancer dormancy.

19. The method of claim 18, wherein the agent capable of inhibiting EMT is osteoprotegerin (OPG) and binds to RANKL to inhibit the formation of osteoclasts, thereby inhibiting the process of RANKL-mediated awakening of cancer dormancy.

20. The method of claim 18, wherein the agent capable of inhibiting EMT is denosumab, RANK-Fc, OPG-Fc, siRNA, shRNA, crizotinib, or VEGFR2 kinase inhibitor III (CAS 204005-46-9) or combinations thereof.

22. The method of claim 18, wherein the cancer is prostate, kidney, breast, bladder, lung, ovarian, pancreatic, thyroid, liver, gastric, colon or melanoma cancer.

23. The method according to claim 18, wherein the cancer is prostate cancer.

21. (canceled)

24. A cell expressing a target selected from the group consisting of RANKL, an EMT marker, NF-kB, c-Met, VEGFR2, neuropilin-1, Src-kinase, Stat3, Mcl-1, and combinations thereof.

25. A method of identifying a compound that inhibits metastasis, comprising:

providing the cell of claim 24;

contacting the cell with a test compound; and

determining whether metastasis is inhibited in the presence of the test compound,

wherein the decrease of the expression of the target is an indication that the test compound inhibits metastasis or

wherein the decrease of a target'"'"'s upstream signaling components, Src-kinase or Stat3 phosphorylation is an indication that the test compound inhibits metastasis.

26. The method of claim 25, wherein the EMT marker is selected from the group consisting of N-cadherin, vimentin, VEGF, RANKL, c-Met and combinations thereof.

28. The method of claim 25, wherein the cell is a prostate, kidney, breast, bladder, lung, ovarian, pancreatic, thyroid, liver, gastric, colon or melanoma cancer cell.

30. The method of claim 28, wherein the prostate cancer cell is ARCaP_E, ARCaP_M, C4-2, LNCaP, PC3 or MCF7.

31. An animal, comprising the cell of claim 24.

32. The animal of claim 31, wherein the cell is an LNCaP-RANKL cell.

33. The animal of claim 31, wherein the animal is a mouse.

34. A method of identifying a compound that inhibits metastasis, comprising:

providing the animal of claim 31;

contacting the animal with a test compound; and

determining whether metastasis is inhibited in the presence of the test compound.

35. The method of claim 34, wherein the decrease of the expression of the target is an indication that the test compound inhibits metastasis or wherein the decrease of a target'"'"'s upstream signaling components, Src-kinase or Stat3 phosphorylation is an indication that the test compound inhibits metastasis.

36. The method of claim 34, wherein the decrease of metastasis of the cancer in the animal is an indication that the test compound inhibits metastasis.

27. (canceled)

29. (canceled)

37. A method of switching osteolytic bone lesion and/or metastasis to osteoblastic bone lesion and/or metastasis in a subject in need thereof comprising:

providing an agent capable of blocking RANK/RANKL signaling and/or HGF/cMet/VEGF/VEGFR2/neuropilin-1-mediated signaling; and

administering the agent to the subject to switch osteolytic bone lesion and/or metastasis to osteoblastic bone lesion and/or metastasis.

38. The method of claim 37, wherein the agent is selected from the group consisting of denosumab, RANK-Fc, OPG-Fc, siRNA, shRNA, crizotinib, VEGFR2 kinase inhibitor III (CAS 204005-46-9) and combinations thereof.

39-77. -77. (canceled)