DEMETHYLATION THERAPY OF THYROID CARCINOMA

甲状腺癌的去甲基化治疗

基本信息

批准号：
6513603
负责人：
Kenneth Bruce Ain
金额：
$ 5.34万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-04 至 2005-03-31
项目状态：
已结题

项目摘要

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.

描述：（申请人的描述）播散性去分化甲状腺上皮癌是一种终末期疾病，目前尚无有效的全身治疗方法治疗或化疗，作为丧失能力的结果浓缩碘化物，使其无法用放射性碘化物处理。我们的转化研究工作旨在恢复治疗放射性碘对全身治疗的有效性。碘化物的吸收取决于人类碘化钠膜同向转运蛋白（hNIS）的表达。化学剂、分化诱导剂和去甲基化剂，已经能够恢复多种其他肿瘤类型中失去的分化功能。我们的数据表明，去甲基化剂可以恢复 hNIS mRNA 的表达去分化人甲状腺癌细胞系并恢复碘吸收。我们已经证明这可能是 CpG 岛去甲基化的结果 hNIS 基因启动子（或甲状腺特异性转录启动子）因子）在肿瘤样本中。为此，我们假设甲基化诱导的 hNIS 基因转录丢失可通过化学方法逆转使用去甲基化剂或分化诱导剂治疗。这样的疗法应该能够使用放射性碘治疗去分化甲状腺癌。在此外，我们还证明了基因甲基化的相同机制负责 E-钙粘蛋白表达的丧失，E-钙粘蛋白是一种蛋白质，有助于细胞：人甲状腺癌细胞的细胞粘附。 E-钙粘蛋白的恢复表达可能抑制肿瘤侵袭和转移，改善临床疗效甲状腺癌患者的病程。这样，去甲基化的临床应用药剂可以增强治疗放射性碘的有效性和同时减少疾病的进展和传播。这个提议以患者为导向的研究将利用去甲基化药物来恢复或增强甲状腺癌转移患者的放射性碘摄取以前对放射性碘治疗无反应。使用已知的中试试验活性药物，如 5-氮杂胞苷，将通过以下试验进行补充：由细胞培养和异种移植研究确定的其他药物。患者治疗无反应的去分化甲状腺癌转移通常采用姑息性手术切除肉眼肿瘤进行治疗。在这样的对患者的新鲜肿瘤样本进行 hNIS 基因甲基化分析 E-钙粘蛋白表达并培养细胞系。这些分析和在体外研究将允许针对个体患者使用特定药物用于放射性碘治疗和肿瘤调节的目的进展。这种以患者为导向的研究将在以下背景下进行：甲状腺肿瘤学和转化研究的积极指导肿瘤学研究员。