DEMETHYLATION THERAPY OF THYROID CARCINOMA

甲状腺癌的去甲基化治疗

• 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
• 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/6513603
• 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)播散性去分化甲状腺 上皮癌是一种终末期疾病，没有有效的全身治疗。 治疗或化疗，作为丧失能力的结果 浓缩碘，使其无法用放射性碘治疗。 我们的翻译研究努力旨在恢复治疗 放射性碘在全身治疗中的作用。碘摄入量取决于 人钠碘转运蛋白(HNIS)的表达化学制品 分化诱导剂和去甲基化试剂已经能够 在多种其他类型的肿瘤中恢复失去的分化功能。 我们的数据表明，去甲基化药物可以恢复hNIS mRNA的表达。 去分化的人甲状腺癌细胞株和恢复碘摄取。 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 因素)在肿瘤样本中。出于这个原因，我们假设 甲基化诱导的hNIS基因转录缺失是化学可逆的 用脱甲基剂或分化诱导剂治疗。这样的疗法 应使去分化甲状腺癌的放射性碘治疗成为可能。在……里面 此外，我们已经证明了基因甲基化的相同机制是 导致E-钙粘蛋白表达缺失的原因，E-钙粘蛋白是一种有助于 细胞：人甲状腺癌细胞中的细胞黏附。E-钙粘附素的修复 表达可抑制肿瘤侵袭转移，改善临床 甲状腺癌患者的病程。通过这种方式，去甲基化在临床上的应用 药物可增强治疗性放射性碘的有效性和 同时减少疾病的发展和传播。这项建议 以患者为中心的研究将利用去甲基化试剂恢复或 提高甲状腺癌转移患者的放射性碘摄取水平 以前对放射性碘治疗无效。试点试验使用已知的 活性物质，如5-氮胞苷，将补充试验 通过细胞培养和异种移植研究确定的其他药物。病人 无治疗反应的去分化甲状腺癌转移 常采用姑息性手术切除大体肿瘤。在这样的情况下 患者，新鲜的肿瘤样本将分析hNIS基因甲基化和 E-钙粘附素的表达，并培养成细胞系。这些分析和 体外研究将允许针对个别患者的特定药物 用于放射性碘治疗和肿瘤的调节 进步。这种以患者为中心的研究将在以下背景下进行 甲状腺肿瘤学和翻译研究方面的积极指导 肿瘤学研究员。