Chemoprevention of Pituitary Corticotroph Tumors

垂体促肾上腺皮质激素肿瘤的化学预防

基本信息

批准号：
7065189
负责人：
ANTHONY P HEANEY
金额：
$ 7.62万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-11 至 2007-04-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：库欣病是由分泌 ACTH 的垂体肿瘤引起的，由于类固醇产生过多而导致疾病；没有合适的药物疗法，手术切除也不一定能治愈。我们已经证明，分泌ACTH的垂体肿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；三萜类化合物氰基-3,12-二氧杂环己烷-1,9(11)-dien-28-oyl]咪唑 (CDDO-IM) 与 PPAR-gamma 结合，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发挥着关键作用，TZD 广泛用于治疗糖尿病。用 PPAR-γ 配体在体外处理人和小鼠促肾上腺皮质激素垂体肿瘤细胞，抑制肿瘤生长并诱导促肾上腺皮质激素肿瘤细胞凋亡。当用罗格列酮治疗携带皮下异种移植促肾上腺皮质激素肿瘤的无胸腺Nu/Nu小鼠时，5只接受治疗的小鼠中有4只没有形成肿瘤。此外，罗格列酮治疗动物的血浆 ACTH 和皮质酮激素水平较低。此外，给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，我们证明了 PPAR-γ 配体 CDDO-IM 在促肾上腺皮质激素肿瘤细胞中具有有效的抗增殖和促凋亡作用，其浓度比罗格列酮低 1000 倍。该项目将研究 CDDO-IM 在 Rb 杂合子敲除小鼠体内的化学预防作用，该小鼠会产生自发性垂体促肾上腺皮质激素肿瘤。我们还将研究高脂肪饮食对垂体促肾上腺皮质激素肿瘤发展的影响，并研究 CDDO-IM 化学预防性抗炎治疗在促肾上腺皮质激素肿瘤模型中的作用。我们的最终目标是为这些 PPAR-γ 配体作为库欣病的新型药物疗法的临床应用找到理论基础。