DEMETHYLATION THERAPY OF THYROID CARCINOMA

甲状腺癌的去甲基化治疗

• 批准号: 6377284
• 负责人: Kenneth Bruce Ain
• 金额: $ 5.27万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377284
• 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：（申请人的描述）散布了甲状腺 上皮癌是一种终末疾病，没有有效的全身性 治疗或化学疗法，由于失去能力 浓缩碘化物，使其无法用放射性碘化物对其进行处理。 我们的翻译研究工作旨在恢复治疗性 放射碘对全身治疗的有效性。 碘化的摄取取决于 人类碘化膜膜分类器（HNI）的表达。 化学 试剂，分化诱导剂和脱甲基化剂已经能够 在各种其他肿瘤类型中，还原损失的功能。 我们的数据表明，脱甲基化剂可以恢复HNI mRNA的表达 去分化的人甲状腺癌细胞系并恢复碘化物的摄取。 我们已经表明，这可能是CPG岛的脱甲基化的结果 HNIS基因启动子（或甲状腺特异性转录的启动子 肿瘤样品中的因素）。 因此，我们假设 甲基化引起的HNIS基因转录的丧失是可逆的 用脱甲基剂或分化诱导剂治疗。 这种疗法 应启用放射性碘治疗去分化的甲状腺癌。 在 此外，我们已经证明了基因甲基化的相同机制是 负责E-钙粘蛋白表达的丧失，这种蛋白质有助于 细胞：人甲状腺癌细胞中的细胞粘附。 恢复E-钙黏着蛋白 表达可能抑制肿瘤侵袭和转移，改善临床 甲状腺癌患者的病程。 这样，脱甲基化的临床使用 代理商可能会提高治疗性放射碘的有效性和 同时减少疾病的进展和传播。 这提出了 面向患者的研究将利用脱甲基化剂恢复或 增强患者甲状腺癌转移的放射性碘摄取 以前对放射性碘治疗没有反应。 使用已知的试验试验 活性剂（例如5-氮杂丁丁）将接受的试验补充 由细胞培养和异种移植研究定义的其他药物。 患者 与治疗无反应的甲状腺癌转移一起 通常通过姑息性手术切除总肿瘤治疗。 在这样 患者，将分析新鲜肿瘤样品的HNIS基因甲基化和 E-钙粘蛋白表达并为细胞系培养。 这些分析和 体外研究将允许将特定药物靶向单个患者 出于放射性碘治疗和肿瘤的调节目的 进展。 这种面向患者的研究将在 甲状腺肿瘤学和转化研究的积极指导为中心 肿瘤学研究员。