Induction of thyroid iodide-handling gene expression in human cancers
Dual suppression of the MAP kinase and PI3K/Akt pathways showed synergistic or greatly enhanced anti-melanoma cell effects, compared to suppression of a single pathway, including the inhibition of cell proliferation, transformation and invasion, induction of G 0 /G 1 cell cycle arrest and, importantly, cell apoptosis. Remarkably, suppression of either pathway induces the expression of thyroid iodide-handling genes and dual suppression of the two pathways synergistically and robustly induces expression of these genes, accompanied by uptake of radioiodine in the cells. These genes include sodium/iodide symporter, thyroid-stimulating hormone receptor, thyroglobulin, thyroperoxidase, pendrin gene, thyroid transcription factors (e.g., TTF-1, TTF-2, PAX8) and other thyroid genes. Targeting major signaling pathways, such as the MAP kinase and PI3K/Akt pathways, for potent cell death, optionally coupled with induction of thyroid gene expression for adjunct radioiodine ablation therapy may be used for many human cancers, both thyroid and non-thyroid.
1. A method of treating a human cancer in a patient comprising: administering an inhibitor of a MAP kinase pathway protein or its expression to the patient in sufficient amounts to induce expression of one or more iodide-handling genes in the human cancer; and administering radioiodine to the patient.
2. The method of claim 1 wherein the radioiodine is administered subsequent to the administering of the inhibitors.
3. The method of claim 1 wherein the human cancer is a thyroid tumor.
4. The method of claim 1 wherein the human cancer is a melanoma.
5. The method of claim 1 wherein the human cancer is a non-thyroid tumor.
6. The method of claim 1 wherein the cancer is a poorly differentiated or undifferentiated thyroid tumor.
7. The method of claim 1 wherein prior to administration of the inhibitors, the cancer is non-responsive to radioiodine treatment.
8. The method of claim 1 wherein a thyroid stimulating hormone is administered to the patient in an amount sufficient to induce expression of one or more iodide-handling genes in the cancer.
9. The method of claim wherein the one or more iodide-handling genes are selected from the group consisting of the sodium/iodide symporter, thyroid stimulating hormone receptor, thyroglobulin, thyroperoxidase, pendrin, and thyroid transcription factors TTF-1, TTF-2, and PAX8.
10. A method for treating thyroid cancer in a patient who is non-responsive to radioiodine treatment comprising: (a) administering an inhibitor of a MAP kinase pathway protein or its expression to the patient in sufficient amounts to induce expression of one or more iodide-handling genes in the cancer; and (B) administering radioiodine to the patient.
11. The method of claim 1 , wherein the cancer has an activating mutation in the MAP kinase pathway.
12. The method of claim 11 , wherein the cancer has an activating mutation selected from the group consisting of BRAF mutation, RET/PTC rearrangement, Ras mutation, MEK mutation and ERK mutation.
13. The method of claim 1 , wherein the MAP kinase pathway protein inhibitor is selected from the group consisting of CI-1040, PD325901, PD184352, AZD6344, ARRY-142886, RDEA119, RDEA436, RDEA119, PLX4720, BAY43-9006(sorafenib) and U0126.
14. The method of claim 1 , wherein the MAP kinase pathway protein inhibitor is CI-1040.
15. The method of claim 10 , wherein the one or more iodide-handling genes are selected from the group consisting of the sodium/iodide symporter, thyroid stimulating hormone receptor, thyroglobulin, thyroperoxidase, pendrin, and thyroid transcription factors TTF-1, TTF-2, and PAX8.
16. The method of claim 1 , wherein one or more iodide-handling genes is the sodium/iodide symporter gene.