Chemoprevention of Pituitary Corticotroph Tumors

描述(申请人提供)：库兴氏病是由于一种分泌ACTH的脑下垂体瘤，由于类固醇的过度产生而引起的疾病；没有合适的药物治疗方法，手术切除并不总是治愈的。我们已经证明，分泌ACTH的垂体瘤表达丰富的过氧化物酶体增殖物激活受体-γ(PPAR-γ)。PPAR-γ和维甲酸X受体(RXR)形成一个允许的异源二聚体，可以被PPAR-γ和/或RXR特异性配体激活，以调节靶基因的转录。一些天然存在的和合成的PPAR-γ配体，包括噻唑烷二酮(TZD)，罗格列酮，非TZD，GW7845，以及三萜类化合物，氰基-3，12-二氧杂环烷-1，9(11)-二烯-28-甲基咪唑(CDDO-IM)与PPAR-γ结合，以调节多种作用。PPAR-γ激活在脂肪生成、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促肾上腺皮质细胞瘤细胞，抑制肿瘤生长，并诱导促肾上腺皮质激素肿瘤细胞凋亡。用罗格列酮治疗皮下移植的裸鼠NU/NU小鼠时，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，其中一名患者的24小时尿皮质醇水平降低了约55%，另一名患者的皮质醇水平恢复正常。最近，我们用比罗格列酮低1000倍的浓度证明了PPAR-γ配体CDDO-IM在促皮质激素肿瘤细胞中具有强大的抗增殖和促凋亡作用。本项目将检测CDDO-IM在Rb杂合子基因敲除小鼠中的化学预防作用，该小鼠患有自发性垂体促肾上腺皮质激素肿瘤。我们还将研究高脂饮食对垂体促肾上腺皮质细胞肿瘤发展的影响，并研究CDDO-IM在促肾上腺皮质细胞肿瘤模型中的化学预防性抗炎治疗的作用。我们的最终目标是为这些PPAR-伽马配体作为库欣病的一种新的药物疗法的临床应用提供理论基础。

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.