GSK3-beta Signaling in Medullary Thyroid Cancer

甲状腺髓样癌中的 GSK3-β 信号转导

• 批准号: 8044830
• 负责人: HERBERT CHEN
• 金额: $ 26.41万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-18 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044830
• 关键词: Abdominal Pain; Accounting; Animal Model; Animals; Biology; Calcitonin; Data Analyses; Diarrhea; Disease; Distant Metastasis; Flushing; Growth; Health; Hormones; Human; In Vitro; Lithium; Lithium Chloride; Liver; Lymph Node Dissections; Malignant neoplasm of thyroid; Mediating; Microscopic; Mus; Mutation; Neck; Neuroendocrine Tumors; Operative Surgical Procedures; Outcome; Patients; Production; Prognostic Marker; Proteins; Recurrence; Recurrent disease; Research; Role; Sampling; Signal Pathway; Signal Transduction; Somatotropin; Structure of thyroid parafollicular cell; Symptoms; Therapeutic; Thyroid Gland; Thyroidectomy; Tissue Sample; Tissues; Tumor-Derived; airway obstruction; cancer cell; cell growth; glycogen synthase kinase 3 beta; glycogen synthase kinase 3 beta inhibitor; human tissue; improved; in vivo; in vivo Model; insight; medullary thyroid carcinoma; member; novel strategies; thyroid neoplasm; tumor; tumor growth

DESCRIPTION (provided by applicant): Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin-producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. While surgery is the only potentially curative therapy for patients with MTC, almost all patients will have persistent or recurrent disease after total thyroidectomy and central lymph node dissection. Moreover, there is no effective alternative to treat many of the debilitating symptoms associated with incurable MTC such as airway obstruction, flushing, abdominal pain and diarrhea. We have shown that activation of raf-1 through inhibition of GSK3B markedly suppresses cellular growth and reduces hormone secretion in human MTC cells in vitro and in vivo. In this proposal, we will explore the potential to utilize GSK3B inhibitors such as lithium to improve surgical outcomes for patient with metastatic MTC. In the first aim, we will develop 2 animal models of recurrent/persistent MTC to determine if GSK3B inhibitors will inhibit tumor growth and suppress hormone production in vivo. In the second aim, we plan to characterize a large number of human thyroid tumor samples, including MTC, and normal thyroid tissue for expression of raf-1 and GSK3B signaling pathway members. The data from these analyses will help predict which patients may be more likely to respond to lithium and other GSK inhibiting compounds. In the third aim, we will delineate the role of GSK3B in raf-1-mediated growth suppression and hormone inhibition. We have found that raf-1 activation also results in an increase in phosphorylated, inactive GSK3B, and that treatment of MTC cells with GSK3B inhibitors, such as lithium chloride and SB216763, can recapitulate the effects of raf-1. We will determine whether or not raf-1-mediated growth and hormone suppression is dependent upon GSK3B inhibition, and if GSK3B is the main downstream target of raf-1. In summary, the studies in this proposal represent a novel approach to understanding the biology of MTC, and may provide new insights to treating and palliating this disease. PUBLIC HEALTH RELEVANCE: Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin- producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. While surgery is the only potentially curative therapy for patients with MTC, almost all patients will have persistent or recurrent disease after total thyroidectomy and central lymph node dissection. Moreover, there is no effective alternative to treat many of the debilitating symptoms associated with incurable MTC. We have shown that activation of raf-1 through inhibition of glycogen synthase kinase-3-beta (GSK3B) markedly suppresses cellular growth and reduces hormone secretion in human MTC cells in vitro and in vivo. In this proposal, we will explore the potential to utilize GSK3B inhibitors to improve surgical outcomes for patients with metastatic MTC.

描述（由申请人提供）：甲状腺癌（MTC）是一种神经内分泌肿瘤，它源自产生甲性甲状腺的甲状腺C细胞，占甲状腺癌病例的3-5％。虽然手术是MTC患者唯一的潜在治疗疗法，但几乎所有患者在全甲状腺切除术和中枢淋巴结清扫术后都将患有持续性或复发性疾病。此外，没有有效的替代方法可以治疗与无法治愈的MTC相关的许多使人衰弱的症状，例如气道阻塞，冲洗，腹痛和腹泻。我们已经表明，通过抑制GSK3b激活RAF-1可以显着抑制细胞生长，并减少人MTC细胞在体外和体内的激素分泌。在此提案中，我们将探索利用GSK3B抑制剂（例如锂）来改善转移性MTC患者的手术结局的潜力。在第一个目标中，我们将开发2种复发/持续性MTC的动物模型，以确定GSK3B抑制剂是否会抑制肿瘤的生长并抑制体内激素的产生。在第二个目标中，我们计划表征大量人类甲状腺肿瘤样品，包括MTC和正常甲状腺组织，以表达RAF-1和GSK3B信号通路成员。这些分析的数据将有助于预测哪些患者可能更有可能对锂和其他gsk抑制化合物做出反应。在第三个目标中，我们将描述GSK3B在RAF-1介导的生长抑制和激素抑制中的作用。我们发现RAF-1激活还会导致磷酸化的，无活跃的GSK3B的增加，并且使用GSK3B抑制剂（例如氯化锂和SB216763）对MTC细胞进行处理可以概括RAF-1的作用。我们将确定RAF-1介导的生长和激素抑制是否取决于GSK3B的抑制作用，以及GSK3B是否是RAF-1的主要下游靶标。总而言之，该提案中的研究代表了一种理解MTC生物学的新方法，并可能为治疗和姑息这种疾病提供新的见解。公共卫生相关性：髓质甲状腺癌（MTC）是一种神经内分泌肿瘤，源自降钙素的甲状腺C细胞，占甲状腺癌病例的3-5％。虽然手术是MTC患者唯一的潜在治疗疗法，但几乎所有患者在全甲状腺切除术和中枢淋巴结清扫术后都将患有持续性或复发性疾病。此外，没有有效的替代方法可以治疗与无法治愈的MTC相关的许多使人衰弱的症状。我们已经表明，通过抑制糖原合酶激酶-3-β（GSK3B）的激活，显着抑制了细胞的生长并减少了人类MTC细胞中体外和体内的激素分泌。在此提案中，我们将探讨利用GSK3B抑制剂来改善转移性MTC患者的手术结局的潜力。