Treatment of metastatic tumors
The present invention is directed to methods and methods for the treatment, inhibition and/or reduction, and detection of metastatic tumors. In some embodiments, the inventive methods include systemic (e.g., intravenous) administration of a chlorotoxin agent that may or may not be labeled. In some embodiments, the inventive methods allow treatment, inhibition and/or reduction, and detection of metastases in the brain. In some embodiments, neovascularization is inhibited and/or newly formed vessels are caused to regress.
1. A method comprising a step of administering an effective dose of a chlorotoxin agent to an individual having at least one metastasis, wherein the chlorotoxin agent is at least 90% identical to an amino acid sequence set forth in SEQ ID NO: 1, wherein the metastasis arose from at least one primary tumor, such that the chlorotoxin agent selectively targets at least one metastasis in that it targets metastatic cancer cells over normal cells.
2. The method of claim 1 , wherein the chlorotoxin agent is administered systemically.
3. The method of claim 2 , wherein the chlorotoxin agent is administered intravenously.
4. The method of claim 1 , wherein the chlorotoxin agent binds to at least one tumor metastasis that is located in the brain.
5. The method of claim 1 , wherein the chlorotoxin agent comprises a chlorotoxin moiety selected from the group consisting of chlorotoxin, biologically active chlorotoxin subunits, and chlorotoxin derivatives.
6. The method of claim 1 , wherein the chlorotoxin agent comprises a chlorotoxin moiety associated with at least one therapeutic moiety.
7. The method of claim 6 , wherein the chlorotoxin moiety and therapeutic moiety are directly covalently associated.
8. The method of claim 6 , wherein the chlorotoxin moiety and therapeutic moiety are fused to form a fusion protein.
9. The method of claim 6 , wherein the chlorotoxin moiety and therapeutic moiety are covalently associated through a linker.
10. The method of claim 6 , wherein the therapeutic moiety comprises an anti-cancer agent.
11. The method of claim 6 , wherein the therapeutic moiety comprises a cytostatic agent.
12. The method of claim 6 , wherein the therapeutic moiety comprises a cytotoxic agent.
13. The method of claim 12 , wherein the cytotoxic agent is selected from the group consisting of toxins, bioactive proteins, chemotherapeutics, antibiotics, nucleolytic enzymes, and radioisotopes.
14. The method of claim 13 , wherein the cytotoxic agent comprises a radioisotope.
15. The method of claim 14 , wherein the radioisotope comprises iodine-131 ( 131 I).
16. The method of claim 10 , wherein the anti-cancer agent is selected from the group consisting of alkylating agents, purine antagonists, pyrimidine antagonists, plant alkaloids, intercalating antibiotics, aromatase inhibitors, anti-metabolites, mitotic inhibitors, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
17. The method of claim 10 , wherein the anti-cancer agent comprises a nucleic acid agent that is between about 5 and 2000 nucleotides long.
18. The method of claim 17 , wherein the nucleic acid agent comprises an antisense agent.
19. The method of claim 17 , wherein the nucleic acid agent encodes an antisense agent.
20. The method of claim 17 , wherein the nucleic acid agent acts as a vector that delivers an antisense agent when introduced into a cell.
21. The method of claim 17 , wherein the nucleic acid agent comprises an inhibitory RNA.
22. The method of claim 17 , wherein the nucleic acid agent encodes an inhibitory RNA.
23. The method of claim 17 , wherein the nucleic acid agent comprises a vector that delivers an inhibitory RNA when introduced into a cell.
24. The method of claim 1 , wherein the primary tumor is a solid tumor.
25. The method of claim 1 , wherein the primary tumor is a refractory tumor.
26. The method of claim 1 , wherein the primary tumor is a recurrent tumor.
27. The method of claim 1 , wherein the primary tumor is a member of the group consisting of lung cancer, bone cancer, liver cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the sexual or reproductive organs, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney, renal cell carcinoma, neoplasms of the central nervous system (CNS), neuroectodermal cancer, spinal axis tumors, glioma, meningioma, and pituitary adenoma.
28. The method of claim 27 , wherein the primary tumor is cutaneous or intraocular melanoma.
29. The method of claim 1 , wherein the primary tumor is a tumor of neuroectodermal origin.
30. The method of claim 29 , wherein the tumor of neuroectodermal origin is a member of the group consisting of glioma, meningioma, ependymoma, medulloblastoma, neuroblastoma, ganglioma, pheochromocytoma, melanoma, peripheral primitive neuroectodermal tumor, small cell carcinoma of the lung, and Ewing's sarcoma.
31. The method of claim 30 , wherein the tumor of neuroectodermal origin is glioma.
32. The method of claim 1 , wherein the step of administering comprises administering at least one dose of chlorotoxin agent, wherein the dose comprises between approximately 0.01 mg/kg and approximately 5 mg/kg.
33. The method of claim 1 , further comprising a step of detecting at least one metastasis prior to administering the chlorotoxin agent to the individual.
34. The method of claim 1 , further comprising administering a chemotherapeutic agent to the individual.
35. The method of claim 34 , wherein the chemotherapeutic agent is selected from the group consisting of alkylating agents, purine antagonists, pyrimidine antagonists, plant alkaloids, intercalating antibiotics, aromatase inhibitors, anti-metabolites, mitotic inhibitors, growth factor inhibitor, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones and anti-androgens.
36. The method of claim 1 , wherein neovasculature of the at least one metastasis regresses.
37. The method of claim 1 , wherein neovascularization is inhibited.
38. The method of claim 1 , wherein migration of at least one cell in the primary tumor is inhibited.
39. The method of claim 1 , wherein the chlorotoxin agent is covalently attached to a polymer.
40. The method of claim 39 , wherein the polymer is polyethylene glycol (PEG).