DEMETHYLATION THERAPY OF THYROID CARCINOMA

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DESCRIPTION: (Applicant's Description) Disseminated dedifferentiated thyroid epithelial carcinoma is a terminal disease with no effective systemic treatment or chemotherapy, as a consequence of the loss of the ability to concentrate iodide, rendering it unable to be treated with radioactive iodide. Our translational research efforts aim to restore the therapeutic effectiveness of radioiodine for systemic therapy. Iodide uptake depends upon expression of the human sodium-iodide membrane symporter (hNIS). Chemical agents, differentiation inducers and demethylation agents, have been able to restore lost differentiated functions in a wide variety of other tumor types. Our data show that demethylation agents can restore expression of hNIS mRNA in dedifferentiated human thyroid cancer cell lines and restore iodide uptake. We have shown that this is likely consequent to demethylation of CpG islands of the hNIS gene promoter (or the promoters of thyroid-specific transcription factors) in tumor samples. For this reason, we hypothesize that methylation-induced loss of hNIS gene transcription is reversible by chemical therapy with demethylating agents or differentiation inducers. Such therapy should enable radioiodide treatment of dedifferentiated thyroid cancers. In addition, we have demonstrated that the same mechanism of gene methylation is responsible for loss of expression of E-cadherin, a protein contributing to cell:cell adhesion in human thyroid cancer cells. Restoration of E-cadherin expression may suppress tumor invasion and metastasis, improving the clinical course of thyroid cancer patients. In this way, clinical use of demethylation agents may enhance the effectiveness of therapeutic radioiodine and simultaneously diminish the progression and spread of disease. This proposed patient-oriented research will utilize demethylation agents to restore or enhance radioiodine uptake in thyroid carcinoma metastases of patients previously unresponsive to radioiodine treatment. Pilot trials using known active agents, such as 5-azacytidine, will be supplemented with trials of additional agents defined by cell culture and xenograft studies. Patients with therapeutically-unresponsive dedifferentiated thyroid cancer metastases are often treated with palliative surgical resection of gross tumor. In such patients, fresh tumor samples will be analyzed for hNIS gene methylation and E-cadherin expression and cultured for cell lines. These analyses and in vitro studies will permit targeting of specific agents to individual patients for the purposes of both radioiodine therapy and modulation of tumor progression. Such patient-oriented research will proceed in the context of active mentorship in thyroid oncology and translational research centered on Oncology fellows.