Somatostatin receptor-based cancer therapy
View Patent ↗Methods and composition for cell-based therapy as well as somatostatin receptor-based therapy are described. For example, in certain aspects methods for administering an anti-tumor therapy using a signaling defective somatostatin receptor mutant are described. Furthermore, the invention provides compositions and methods involve a somatostatin constitutively active somatostatin receptor mutant.
1. A method of treating a tumor, comprising the steps of:
a) providing stem cells, immune cells or fibroblast cells having the ability to migrate to and localize to a tumor upon parenteral administration to a subject having a tumor, wherein the cells are engineered cells that comprise an exogenous expression construct having a nucleic acid sequence encoding a somatostatin receptor, wherein the somatostatin receptor is a native somatostatin receptor or a mutant thereof, wherein the receptor comprises a ligand binding domain that is competent to bind a somatostatin receptor ligand;
b) introducing the engineered cells parenterally to a subject having a tumor; and
c) administering to the subject a somatostatin receptor ligand and an anti-tumor therapeutic that specifically binds the ligand and that is effective to kill the engineered cells and thereby effect a damage on the tumor, whereby the tumor is treated.
2. The method of claim 1 , wherein the somatostatin receptor is a signaling defective somatostatin receptor mutant.
3. The method of claim 2 , wherein the mutant has at least trans-membrane domains III-VII of a native somatostatin receptor.
4. The method of claim 3 , wherein the somatostatin receptor has a C-terminal deletion.
5. The method of claim 4 , wherein the somatostatin receptor is human SSTR2 delta 314 mutant with the sequence of amino acid 1-314 of SEQ ID NO:6.
6. The method of claim 2 , wherein the somatostatin receptor is a SSTR2 mutant.
7. The method of claim 1 , wherein the expression construct further comprises a second coding sequence, wherein the second coding sequence is a protein tag gene, reporter gene, a therapeutic gene, a signaling sequence, or a trafficking sequence.
8. The method of claim 1 , wherein the tumor is a breast tumor, a lung tumor, a prostate tumor, an ovarian tumor, a brain tumor, a liver tumor, a cervical tumor, a colon tumor, a renal tumor, a skin tumor, a head and neck tumor, a bone tumor, an esophageal tumor, a bladder tumor, a uterine tumor, a lymphatic tumor, a stomach tumor, a pancreatic tumor, or a testicular tumor.
9. The method of claim 1 , wherein the therapeutic comprises a therapeutic radionuclide.
10. The method of claim 9 , wherein the therapeutic radionuclide is a β − particle emitter.
11. The method of claim 10 , wherein the therapeutic radionuclide comprises 177 Lu or 90 Y.
12. The method of claim 1 , wherein the therapeutic is coupled to a ligand that specifically binds the somatostatin receptor or receptor mutant.
13. The method of claim 12 , wherein the ligand is a somatostatin analog.
14. The method of claim 12 , wherein the ligand comprises a chelator molecule.
15. The method of claim 14 , wherein the chelator molecule is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or diethylene triamine pentaacetic acid (DTPA).
16. The method of either of claim 12 or 13 , wherein the ligand is octreotate or octreotide.
17. The method of claim 1 , further comprising tracking the cells or expression of the expression construct in the subject.
18. The method of claim 1 , further comprising imaging the cells.
19. The method of claim 18 , further comprising imaging the cells via MRI, MR spectroscopy, radiography, CT, ultrasound, planar gamma camera imaging, SPECT, PET, nuclear medicine-based imaging, optical imaging using visible light, optical imaging using luciferase, optical imaging using a fluorophore, optical imaging, imaging using near infrared light, imaging using infrared light, photoacoustic imaging or thermoacoustic imaging.
20. The method of claim 1 , further comprising administering to the subject a detectable moiety coupled to a ligand that specifically binds the somatostatin receptor.
21. The method of claim 1 , wherein the tumor is further defined as a solid tumor.
22. The method of claim 21 , wherein the solid tumor is a sarcoma or lymphoma.
23. The method of claim 21 , wherein the solid tumor is a neuroendocrine tumor.
24. The method of claim 21 , wherein the solid tumor is a breast tumor, a lung tumor, a prostate tumor, an ovarian tumor, a brain tumor, a liver tumor, a cervical tumor, a colon tumor, a renal tumor, a skin tumor, a head and neck tumor, a bone tumor, an esophageal tumor, a bladder tumor, a uterine tumor, a lymphatic tumor, a stomach tumor, a pancreatic tumor, or a testicular tumor.
25. The method of claim 1 , wherein the cells are mesenchymal stem cells.
26. The method of claim 1 , wherein the cells are lymphocytes.
27. The method of claim 1 , wherein the cells are cells engineered to localize to a tumor expressing an antigen or chemoattractant.
28. The method of claim 1 , wherein the cells are injected into the subject intravenously, intraarterially, intratumorally or intraperitoneally.