DEMETHYLATION THERAPY OF THYROID CARCINOMA

甲状腺癌的去甲基化治疗

• 批准号: 6728252
• 负责人: Kenneth Bruce Ain
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-04 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6728252
• 关键词: DNA methylation; athymic mouse; azacitidine; butyrates; cadherins; cell line; clinical research; combination cancer therapy; combination chemotherapy; gene induction /repression; genetic promoter element; human subject; human therapy evaluation; hydroxyurea; iodine; membrane transport proteins; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; neoplasm /cancer radionuclide therapy; phenylacetates; sodium ion; thyroid neoplasm; thyroxine

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：（申请人描述）弥漫性去分化甲状腺 上皮癌是一种晚期疾病， 治疗或化疗，由于丧失的能力， 浓缩碘化物，使其不能用放射性碘化物处理。 我们的转化研究工作旨在恢复治疗 放射性碘全身治疗有效性。 碘的吸收取决于 人钠-碘膜同向转运体（hNIS）的表达。 化学 分化诱导剂和去甲基化剂已经能够 恢复各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， 去分化的人甲状腺癌细胞系和恢复碘摄取。 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的启动子 因子）。 因此，我们假设， 甲基化诱导的hNIS基因转录的损失是可逆的， 用去甲基化剂或分化诱导剂治疗。 这种治疗 应该能够使去分化甲状腺癌的放射性碘治疗。 在 此外，我们已经证明，同样的基因甲基化机制， 负责E-钙粘蛋白表达的丧失，E-钙粘蛋白是一种有助于 人甲状腺癌细胞中的细胞：细胞粘附。 E-钙粘蛋白的恢复 表达可抑制肿瘤的侵袭和转移，提高临床疗效。 甲状腺癌的治疗方法 这样，临床上使用去甲基化 试剂可以增强治疗性放射性碘的有效性， 同时减少疾病的发展和传播。 这一拟议 以患者为导向的研究将利用去甲基化剂来恢复或 提高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 活性药物，如5-氮杂胞苷，将补充试验， 通过细胞培养和异种移植研究确定的其他药剂。 患者 治疗无效的去分化甲状腺癌转移 通常采用姑息性手术切除肿瘤。 以这样 在患者中，将分析新鲜肿瘤样品的hNIS基因甲基化， E-钙粘蛋白表达并培养细胞系。 这些分析和 体外研究将允许将特异性药剂靶向个体患者 为了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导师制， 肿瘤学研究员