Chemoprevention of Pituitary Corticotroph Tumors

描述（由申请人提供）：库欣病是一种分泌acth的垂体肿瘤，由于过量的类固醇产生而导致疾病；没有合适的药物治疗，手术切除并不总是能治愈。我们已经证明垂体acth分泌瘤表达丰富的过氧化物酶体增殖物激活受体- γ (ppar - γ)。ppar - γ和类视黄醇X受体（RXR）形成一个允许的异二聚体，可以被ppar - γ和/或RXR特异性配体激活，以调节靶基因的转录。几种天然存在和合成的ppar - γ配体，包括噻唑烷二酮（TZD），罗格列酮；非tzd， GW7845；而三萜类化合物氰-3,12-二氧齐烷-1,9(11)-二烯-28-酰基]咪唑（CDDO-IM）结合ppar - γ，调节多种作用。ppar - γ激活在脂肪形成、葡萄糖代谢和胎盘功能中起着关键作用，TZD被广泛用于治疗糖尿病。ppar - γ配体体外处理人和小鼠垂体促皮质瘤细胞，抑制肿瘤生长，诱导促皮质瘤细胞凋亡。当含有皮下异种移植皮质性肿瘤的胸腺Nu/ Nu小鼠接受罗格列酮治疗时，5只小鼠中有4只未发生肿瘤。此外，罗格列酮治疗的动物血浆ACTH和皮质酮激素水平较低。此外，两名库欣病患者服用罗格列酮后，其中一名患者24小时尿皮质醇水平降低约55%，另一名患者皮质醇水平正常化。最近，我们已经证明ppar - γ配体CDDO-IM在促皮质性肿瘤细胞中具有有效的抗增殖和促凋亡作用，使用浓度比罗格列酮低1000倍。本项目将研究CDDO-IM在Rb杂合子敲除小鼠体内发生自发性垂体促皮质性肿瘤的化学预防作用。我们还将研究高脂肪饮食对垂体促皮质性肿瘤发展的影响，并研究CDDO-IM化学预防抗炎治疗在促皮质性肿瘤模型中的作用。我们的最终目标是为这些ppar - γ配体作为库欣病的一种新的药物治疗方法的临床应用开发一个基本原理。

DESCRIPTION (provided by applicant): Cushing's disease, due to an ACTH-secreting pituitary tumor, causes illness due to excess steroid production; no suitable drug therapies are available, and surgical excision, is not always curative. We have demonstrated that ACTH-secreting pituitary tumors express abundant peroxisome proliferators activated receptor-gamma (PPAR-gamma). PPAR-gamma and the retinoid X receptor (RXR) form a permissive heterodimer, that can be activated by either PPAR-gamma and/ or RXR-specific ligands to regulate target gene transcription. Several natural occurring and synthetic PPAR-gamma ligands, including the thiazolidinedione (TZD), rosiglitazone; the non-TZD, GW7845; and the triterpenoid, cyano-3,12- dioxooleaneana-1,9(11)-dien-28-oyl]imidazole (CDDO-IM) bind PPAR-gamma, to regulate multiple actions. PPAR-gamma activation plays a critical role in adipogenesis, glucose metabolism, and placental function, and TZD's are widely used to treat diabetes. Treatment of human and mouse corticotroph pituitary tumor cells in vitro with PPAR-gamma ligands, inhibited tumor growth, and induced corticotroph tumor apoptosis. When athymic Nu/ Nu mice harboring subcutaneous xenografted corticotroph tumors, were treated with rosiglitazone, 4 of 5 treated mice did not develop tumors. Furthermore, plasma ACTH and corticosterone hormone levels were lower in rosiglitazone-treated animals. In addition, rosiglitazone, given to two patients with Cushing's disease, decreased 24 hour urinary cortisol levels by approximately 55% in one patient, and normalized cortisol levels in the second patient. Recently, we have demonstrated potent anti-proliferative, and pro-apoptotic actions of the PPAR-gamma ligand CDDO-IM in corticotroph tumor cells, using 1000-fold lower concentrations than rosiglitazone. This project will examine the chemopreventative actions of CDDO-IM in vivo in the Rb heterozygote knock-out mouse that develops spontaneous pituitary corticotroph tumor. We will also examine the effects of a high fat diet on pituitary corticotroph tumor development, and examine the role of chemopreventative anti-inflammatory treatment with CDDO-IM in the corticotroph tumor model. Our ultimate goal is to develop a rationale for clinical application of these PPAR-gamma ligands as a novel medical therapy in Cushing's disease.