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:
  • 金额:
    $ 7.62万
  • 依托单位:
  • 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(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。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting pituitary tumors.
针对垂体肿瘤。
  • DOI:
    10.1159/000110608
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Heaney,AnthonyP
  • 通讯作者:
    Heaney,AnthonyP
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ANTHONY P HEANEY其他文献

ANTHONY P HEANEY的其他文献

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{{ truncateString('ANTHONY P HEANEY', 18)}}的其他基金

Development of a patient-derived tumoroid culture system to explore novel medical treatments for refractory prolactinomas
开发患者源性肿瘤培养系统,探索难治性泌乳素瘤的新疗法
  • 批准号:
    10643450
  • 财政年份:
    2023
  • 资助金额:
    $ 7.62万
  • 项目类别:
Identification of TR4 Modulators for Treatment of Cushing Disease.
用于治疗库欣病的 TR4 调节剂的鉴定。
  • 批准号:
    10199436
  • 财政年份:
    2021
  • 资助金额:
    $ 7.62万
  • 项目类别:
Development of 3-dimensional human pituitary corticotroph tumor cultures as a preclinical model for drug discovery
开发 3 维人垂体促肾上腺皮质激素肿瘤培养物作为药物发现的临床前模型
  • 批准号:
    10448514
  • 财政年份:
    2021
  • 资助金额:
    $ 7.62万
  • 项目类别:
Development of 3-dimensional human pituitary corticotroph tumor cultures as a preclinical model for drug discovery
开发 3 维人垂体促肾上腺皮质激素肿瘤培养物作为药物发现的临床前模型
  • 批准号:
    10653709
  • 财政年份:
    2021
  • 资助金额:
    $ 7.62万
  • 项目类别:
Development of 3-dimensional human pituitary corticotroph tumor cultures as a preclinical model for drug discovery
开发 3 维人垂体促肾上腺皮质激素肿瘤培养物作为药物发现的临床前模型
  • 批准号:
    10297675
  • 财政年份:
    2021
  • 资助金额:
    $ 7.62万
  • 项目类别:
Refined Fructose Promotes Pancreatic Cancer Growth
精制果糖促进胰腺癌生长
  • 批准号:
    7904018
  • 财政年份:
    2007
  • 资助金额:
    $ 7.62万
  • 项目类别:
Refined Fructose Promotes Pancreatic Cancer Growth
精制果糖促进胰腺癌生长
  • 批准号:
    8137007
  • 财政年份:
    2007
  • 资助金额:
    $ 7.62万
  • 项目类别:
Refined Fructose Promotes Pancreatic Cancer Growth
精制果糖促进胰腺癌生长
  • 批准号:
    7667840
  • 财政年份:
    2007
  • 资助金额:
    $ 7.62万
  • 项目类别:
Refined Fructose Promotes Pancreatic Cancer Growth
精制果糖促进胰腺癌生长
  • 批准号:
    7502595
  • 财政年份:
    2007
  • 资助金额:
    $ 7.62万
  • 项目类别:
Refined Fructose Promotes Pancreatic Cancer Growth
精制果糖促进胰腺癌生长
  • 批准号:
    7371529
  • 财政年份:
    2007
  • 资助金额:
    $ 7.62万
  • 项目类别:

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