GSK3-beta Signaling in Medullary Thyroid Cancer

描述(申请人提供)：甲状腺髓样癌(MTC)是一种神经内分泌肿瘤，起源于产生降钙素的甲状腺C细胞，占甲状腺癌病例的3%-5%。虽然手术是治疗MTC的唯一可能的治疗方法，但几乎所有患者在全甲状腺切除和中央淋巴清扫后都会有持续性或复发的疾病。此外，目前还没有有效的替代疗法来治疗与无法治愈的MTC相关的许多令人衰弱的症状，如呼吸道阻塞、潮红、腹痛和腹泻。我们已经证明，通过抑制GSK3B激活RAF-1显著抑制了人MTC细胞的生长，减少了体内和体外的激素分泌。在这项提案中，我们将探索利用GSK3B抑制剂如锂来改善转移性MTC患者的手术结果的潜力。在第一个目标中，我们将建立两种复发/持续性MTC的动物模型，以确定GSK3B抑制剂在体内是否会抑制肿瘤生长和抑制激素的产生。在第二个目标中，我们计划表征大量的人甲状腺肿瘤样本，包括MTC和正常甲状腺组织中RAF-1和GSK3B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可能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的激活也会导致磷酸化的、非活性的GSK3B的增加，而用GSK3B抑制剂，如氯化锂和SB216763处理MTC细胞，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依赖于GSK3B的抑制，以及GSK3B是否是RAF-1的主要下游靶点。综上所述，本提案中的研究代表了一种理解MTC生物学的新方法，并可能为治疗和缓解这种疾病提供新的见解。公共卫生意义：甲状腺髓样癌(MTC)是一种神经内分泌肿瘤，起源于产生降钙素的甲状腺C细胞，占甲状腺癌病例的3%-5%。虽然手术是治疗MTC的唯一可能的治疗方法，但几乎所有患者在全甲状腺切除和中央淋巴清扫后都会有持续性或复发的疾病。此外，目前还没有有效的替代方案来治疗与无法治愈的MTC相关的许多令人衰弱的症状。我们发现在体外和体内，RAF-1通过抑制糖原合成酶-3-β(GSK3B)的激活而显著抑制人MTC细胞的生长和减少激素的分泌。在这项提案中，我们将探索利用GSK3B抑制剂来改善转移性MTC患者的手术结果的可能性。

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.