DIAGNOSIS AND TREATMENT OF TUMORS
The present invention is directed to methods and compositions for the treatment and diagnosis of neuroectodermally-derived tumors, such as gliomas. The inventive methods of treatment generally include local (e.g., intracavitary) administration of a chloroxotoxin moiety conjugated to a cytotoxic moiety to a patient. Also provided are diagnostic methods for screening neoplastic neuroectodermal tumors.
1 . A method of treating an individual having a neuroectodermally-derived tumor, the method comprising a step of: administering an effective amount of a cytotoxic chlorotoxin conjugate to the individual, wherein the cytotoxic chlorotoxin conjugate comprises at least one chlorotoxin moiety associated with at least one cytotoxic moiety.
2 . The method of claim 1 , wherein the neuroectodermally-derived tumor 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, Ewing's sarcoma, and metastatic tumor of neuroectodermal origin in the brain.
3 . The method of claim 1 , wherein the neuroectodermally-derived tumor is located in the brain.
4 . The method of claim 3 , wherein the neuroectodermally-derived tumor is a glioma.
5 . The method of claim 4 , wherein the glioma is a high-grade glioma.
6 . The method of claim 5 , wherein the high-grade glioma is a recurrent high-grade glioma.
7 . The method of claim 1 , wherein the neuroectodermally-derived tumor is a refractory tumor.
8 . The method of claim 1 , wherein the chlorotoxin moiety is covalently associated with the cytotoxic moiety.
9 . (canceled)
10 . The method of claim 1 , wherein the cytotoxic moiety is selected from the group consisting of toxins, bioactive proteins, chemotherapeutic antibiotics, nucleolytic enzymes, and radioisotopes.
11 . The method of claim 10 , wherein the cytotoxic moiety comprises a member of the group consisting of gelonin, ricin, saponin, Pseudomonas exotoxin, pokeweed antiviral protein, diphtheria toxin, and complement proteins.
12 . The method of claim 10 , wherein the cytotoxic moiety comprises a radioisotope.
13 . The method of claim 12 , wherein the cytotoxic moiety comprises iodine-131 ( 131 I).
14 . The method of claim 3 , wherein the step of administering comprises intracavitary administration of at least one dose of cytotoxic chlorotoxin conjugate.
15 . The method of claim 14 , wherein the dose of cytotoxic chlorotoxin conjugate comprises between approximately 0.1 mg and approximately 5.0 mg of chlorotoxin moiety.
16 . The method of claim 15 , wherein the dose of cytotoxic chlorotoxin conjugate comprises approximately 0.25 mg of chlorotoxin moiety, approximately 0.5 mg of chlorotoxin moiety, approximately 1.0 mg of chlorotoxin moiety, approximately 2.0 mg of chlorotoxin moiety, approximately 3.0 mg of chlorotoxin moiety, approximately 4.0 mg of chlorotoxin moiety, or approximately 5.0 mg of chlorotoxin moiety.
17 . The method of claim 14 , wherein the cytotoxic chlorotoxin conjugate comprises 131 I and the dose of cytotoxic chlorotoxin conjugate comprises between approximately 10 mCuries and approximately 50 mCuries of 131 I.
18 . The method of claim 14 , wherein the step of administering comprises intracavitary administration of at least two doses of cytotoxic chlorotoxin conjugate.
19 . (canceled)
20 . The method of claim 18 , wherein each of the doses of cytotoxic chlorotoxin conjugate comprises between approximately 0.1 mg and approximately 5.0 mg of chlorotoxin moiety.
21 . The method of claim 20 , wherein each of the doses of cytotoxic chlorotoxin conjugate comprises approximately 0.25 mg of chlorotoxin moiety, approximately 0.5 mg of chlorotoxin moiety, approximately 1.0 mg of chlorotoxin moiety, approximately 2.0 mg of chlorotoxin moiety, approximately 3.0 mg of chlorotoxin moiety, approximately 4.0 mg of chlorotoxin moiety, or approximately 5.0 mg of chlorotoxin moiety.
22 . The method of claim 18 , wherein the cytotoxic chlorotoxin conjugate comprises 131 I and each of the doses of cytotoxic chlorotoxin conjugate comprises between approximately 10 mCuries and approximately 50 mCuries of 131 I.
23 . The method of claim 1 further comprising administering a chemotherapeutic agent to the individual.
24 . A method of differentiating neuroectodermally-derived neoplastic tumor tissue from non-neoplastic tissue, the method comprising steps of:
contacting a tissue of interest with a diagnostic chlorotoxin agent, wherein the diagnostic chlorotoxin agent comprises at least one chlorotoxin moiety associated with at least one labeling moiety; and
measuring binding of the diagnostic chlorotoxin agent to the tissue of interest, wherein an elevated level of binding, relative to normal tissue, indicates that the tissue of interest is a neuroectodermally-derived tumor tissue.
25 . The method of claim 24 , wherein the labeling moiety comprises a member from the group consisting of a fluorescent agent, a radioisotope, an enzyme, and a paramagnetic metal ion.
26 . The method of claim 24 , wherein the step of measuring binding of the diagnostic chlorotoxin agent to the tissue of interest is performed using a technique selected from the group consisting of fluorescence microscopy, bioluminescence, fluorescent activated cell sorting (FACS), histochemical staining, ELISA, Magnetic Resonance Imaging (MRI), Gamma camera, Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET).
27 . The method of claim 24 , wherein the tissue of interest comprises brain tissue.
28 . The method of claim 24 , wherein the contacting step is performed in vivo or ex vivo.
29 . (canceled)
30 . The method of claim 24 , wherein the tissue of interest originates from an individual suspected of having a neuroectodermally-derived tumor.
31 . The method of claim 30 , wherein the neuroectodermally-derived tumor 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, Ewing's sarcoma, and metastatic tumor of neuroectodermal origin in the brain.
32 . The method of claim 24 , wherein the labeling moiety comprises iodine-131 ( 131 I), iodine-125 ( 125 I), technetium-99m ( 99m Tc) or copper-64 ( 64 Cu).
33 - 34 . (canceled)