GSK3-beta Signaling in Medullary Thyroid Cancer

甲状腺髓样癌中的 GSK3-β 信号转导

• 批准号: 8396621
• 负责人: HERBERT CHEN
• 金额: $ 5.01万
• 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/8396621
• 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）：甲状腺髓样癌（MTC）是一种神经内分泌肿瘤，来源于产生降钙素的甲状腺C细胞，占甲状腺癌病例的3-5%。虽然手术是MTC患者唯一潜在的治愈性治疗方法，但几乎所有患者在甲状腺全切除术和中央淋巴结清扫术后都会有持续或复发的疾病。此外，没有有效的替代方案来治疗与不可治愈的MTC相关的许多衰弱症状，例如气道阻塞、潮红、腹痛和腹泻。我们已经表明，通过抑制GSK 3B激活raf-1显着抑制细胞生长，并减少激素分泌的人MTC细胞在体外和体内。在本提案中，我们将探索利用GSK 3B抑制剂（如锂）改善转移性MTC患者手术结局的可能性。在第一个目标中，我们将开发2种复发性/持续性MTC的动物模型，以确定GSK 3B抑制剂是否会抑制体内肿瘤生长并抑制激素产生。在第二个目标中，我们计划表征大量人类甲状腺肿瘤样本，包括MTC和正常甲状腺组织中raf-1和GSK 3B信号通路成员的表达。这些分析的数据将有助于预测哪些患者更有可能对锂和其他GSK抑制化合物产生反应。在第三个目标中，我们将描述GSK 3B在raf-1介导的生长抑制和激素抑制中的作用。我们已经发现，raf-1激活也导致磷酸化的、无活性的GSK 3B的增加，并且用GSK 3B抑制剂如氯化锂和SB 216763处理MTC细胞可以重现raf-1的作用。我们将确定raf-1介导的生长和激素抑制是否依赖于GSK 3B抑制，以及GSK 3B是否是raf-1的主要下游靶点。总之，本提案中的研究代表了理解MTC生物学的新方法，并可能为治疗和缓解这种疾病提供新的见解。公共卫生关系：甲状腺髓样癌（MTC）是一种神经内分泌肿瘤，来源于产生降钙素的甲状腺C细胞，占甲状腺癌病例的3-5%。虽然手术是MTC患者唯一潜在的治愈性治疗方法，但几乎所有患者在甲状腺全切除术和中央淋巴结清扫术后都会有持续或复发的疾病。此外，没有有效的替代方案来治疗与不可治愈的MTC相关的许多衰弱症状。我们已经表明，通过抑制糖原合成酶激酶-3-β（GSK 3B）的raf-1的激活显着抑制细胞生长，并减少激素分泌的人MTC细胞在体外和体内。在本提案中，我们将探索利用GSK 3B抑制剂改善转移性MTC患者手术结局的潜力。