Chemoprevention of Pituitary Corticotroph Tumors

描述（由申请人提供）：库欣氏病是由分泌ACTH的垂体瘤引起的，由于类固醇产生过多而引起疾病;没有合适的药物治疗，手术切除并不总是治愈的。我们已经证明，促肾上腺皮质激素分泌型垂体瘤表达丰富的过氧化物酶体增殖物激活受体-γ（PPAR-gamma）。PPAR-gamma和类维生素A X受体（RXR）形成允许的异源二聚体，其可以被PPAR-gamma和/或RXR特异性配体激活以调节靶基因转录。几种天然存在的和合成的PPAR-gamma配体，包括噻唑烷二酮（TZD），罗格列酮;非TZD，GW 7845;和三萜类化合物，氰基-3，12-二氧代齐墩果烷-1，9（11）-二烯-28-酰基]咪唑（CDDO-IM）结合PPAR-gamma，以调节多种作用。PPAR-gamma活化在脂肪形成、葡萄糖代谢和胎盘功能中起关键作用，TZD广泛用于治疗糖尿病。在体外用PPAR-gamma配体处理人和小鼠促肾上腺皮质激素垂体瘤细胞，抑制肿瘤生长，并诱导促肾上腺皮质激素肿瘤细胞凋亡。当用罗格列酮治疗皮下移植的促肾上腺皮质激素细胞肿瘤的无胸腺Nu/ Nu小鼠时，5只治疗的小鼠中有4只没有发生肿瘤。此外，罗格列酮给药动物的血浆ACTH和皮质酮激素水平较低。此外，罗格列酮，给予两名患者库欣病，降低24小时尿皮质醇水平约55%，在第二个病人的皮质醇水平正常化。最近，我们已经证明了有效的抗增殖和促凋亡行动的PPAR-gamma配体CDDO-IM在促肾上腺皮质激素肿瘤细胞，使用1000倍的浓度比罗格列酮低。本项目将研究CDDO-IM在Rb杂合子基因敲除小鼠体内的化学预防作用，该小鼠发生自发性垂体促肾上腺皮质激素细胞瘤。我们还将研究高脂饮食对垂体促肾上腺皮质激素细胞肿瘤发展的影响，并研究CDDO-IM在促肾上腺皮质激素细胞肿瘤模型中的化学预防性抗炎治疗的作用。我们的最终目标是开发一个合理的临床应用这些PPAR-gamma配体作为一种新的药物治疗库欣病。

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.