PREOPERATIVE BEXAROTENE TREATMENT FOR CUSHING'S DISEASE

库欣病术前贝沙罗汀治疗

• 批准号: 8167193
• 负责人: MARY L VANCE
• 金额: $ 2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167193
• 关键词: Accounting; Acute; Admission activity; Adrenal gland hypofunction; Aftercare; Agonist; Anterior Pituitary Gland; Apoptosis; Bexarotene; Biochemical; Canis familiaris; Cell Death; Cells; Clinical; Clinical Research; Collection; Complete Blood Count; Computer Retrieval of Information on Scientific Projects Database; Corticotropin; Cultured Tumor Cells; Data; Diagnosis; Disease remission; Dose; FDA approved; Fibrinogen; Funding; Genes; Glucocorticoids; Grant; Histologic; Hour; Human; Hydrocortisone; Hypothyroidism; In Vitro; Individual; Inpatients; Institution; Ketoconazole; Laboratories; Liver; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Methods; Monitor; Morbidity - disease rate; Neutropenia; Nuclear Orphan Receptor; Operative Surgical Procedures; Outcome Measure; Pathologic; Patients; Physiological; Pilot Projects; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Plasma; Population; Pro-Opiomelanocortin; Publishing; RXR; Randomized; Rattus; Renal function; Reporting; Research; Research Personnel; Resources; Retinoids; Safety; Schedule; Signal Transduction; Signs and Symptoms; Source; Thyroid Function Tests; Time; Transcription Factor AP-1; Transfection; Tretinoin; United States National Institutes of Health; Urine; alitretinoin; base; chicken ovalbumin upstream promoter-transcription factor; improved; millimeter; mortality; neoplastic cell; promoter; rat orphan nuclear receptor NR4A1; tissue culture; transcription factor; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Cushing's disease refers to a condition of glucocorticoid exceess caused by an adrenocorticotropic hormone (ACTH) producing pituitary tumor, which account for 10-15% of all pituitary tumors. The majority of corticotroph tumors are microadenomas at the time of diagnosis, and accurate surgical and histologic identification of these tumors can be challenging. ACTH is produced in corticotroph cells within the anterior pituitary via the precursor pro-opiomelanocortin (POMC). In both physiologic and pathologic conditions the promoter for POMC is regulated by multiple transcription factors which include AP-1 and Nurr77. Retinoic acid has been shown to inhibit activation of the POMC promoter in corticotroph tumor cell culture via disruption of Nurr77 transcriptional activity. The expression of the orphan nuclear receptor termed chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) antagonizes retinoic acid signaling, and has been reported to be present in normal corticotroph cells, but lacking in adenomatous corticotroph cells in tissue culture studies. Through the retrospective analysis of 34 human corticotroph tumors we have demonstrated a consistent lack of COUP-TFI in 100% of the microadenomas that were not visible, or measured less than 5 millimeters by preoperative MRI. In total, 85% of all tumors studied showed absence of COUP-TFI. Based on in vitro data from rat and human corticotroph tumors, cells lacking COUP-TFI are vulnerable to retinoid-induced cell death via Nurr77-mediated apoptosis, an effect that is reversed by COUP-TFI gene transfection. In 2006, Castillo et al. published the results of a six-month trial which randomized 44 dogs with Cushing's disease to an RXR agonist (9-cis retinoic acid), or to ketoconazole. RXR agonist therapy outperformed ketoconazole for all endpoints, resulting in normalization of ACTH and cortisol levels in 100% of subjects that completed the study, and improved morbidity and mortality. All of the dogs treated with the RXR agonist remained in remission for the duration of the 6 to 12 month post-treatment followup. Hypothesis and Objectives: We hypothesize that the differential expression of COUP-TFI in normal vs. adenomatous corticotroph cells in human microadenomas identifies a retinoid-sensitive tumor population which is vulnerable to retinoid-induced ACTH-suppression and apoptosis. The objective of this pilot study is to establish the safety and tolerability of short-term therapy with bexarotene in patients with Cushing's disease, and study the clinical, biochemical, and cellular effects of a preoperative five-day course of bexarotene in these patients before undergoing transsphenoidal surgery. The primary biochemical outcome measures will be diurnal plasma ACTH and cortisol, and serial 24-hour urine free cortisol levels. Methods: This pilot study (n = 6 subjects) will involve inpatient admission to our General Clinical Research Center for 5 days prior to scheduled transsphenoidal surgery. During the five days of the study each individual will receive the RXR-agonist bexarotene at the FDA approved dose of 300 mg/m2/day. Clinical signs and symptoms of acute adrenal insufficiency will be monitored routinely throughout each 24-hour period. Baseline and twice-daily biochemical analysis for ACTH and cortisol will be performed. 24-hour urine collection for cortisol will be obtained pre-treatment and in the last 24-hours of treatment. Laboratory safety analysis will include serial comprehensive metabolic panels to monitor liver and kidney function, complete blood count to monitor for neutropenia, as well as thyroid function studies to monitor for central hypothyroidism which can develop with therapy.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 背景：库欣病是指由产生促肾上腺皮质激素（ACTH）的垂体瘤引起的糖皮质激素过量的病症，占所有垂体瘤的10-15%。大多数促肾上腺皮质激素肿瘤在诊断时都是微腺瘤，准确的手术和组织学鉴定这些肿瘤可能具有挑战性。 ACTH 是在垂体前叶内的促肾上腺皮质细胞中通过前体阿黑皮质素原 (POMC) 产生的。在生理和病理条件下，POMC 的启动子受到多种转录因子的调节，包括 AP-1 和 Nurr77。视黄酸已被证明可以通过破坏 Nurr77 转录活性来抑制促肾上腺皮质激素肿瘤细胞培养物中 POMC 启动子的激活。被称为鸡卵白蛋白上游启动子转录因子 I (COUP-TFI) 的孤儿核受体的表达会拮抗视黄酸信号传导，并且据报道存在于正常促肾上腺皮质细胞中，但在组织培养研究中在腺瘤促肾上腺皮质细胞中缺乏。 通过对 34 个人类促肾上腺皮质激素肿瘤的回顾性分析，我们证明 100% 不可见或术前 MRI 测得小于 5 毫米的微腺瘤中始终缺乏 COUP-TFI。 总共，85% 的研究肿瘤显示不存在 COUP-TFI。 根据大鼠和人类促肾上腺皮质激素肿瘤的体外数据，缺乏 COUP-TFI 的细胞很容易通过 Nurr77 介导的细胞凋亡而受到类维生素A诱导的细胞死亡的影响，这种效应可以通过 COUP-TFI 基因转染来逆转。 2006 年，卡斯蒂略等人。发表了一项为期六个月的试验结果，该试验将 44 只患有库欣病的狗随机分配给 RXR 激动剂（9-顺式视黄酸）或酮康唑。 RXR 激动剂疗法在所有终点均优于酮康唑，导致完成研究的受试者 100% 的 ACTH 和皮质醇水平正常化，并改善了发病率和死亡率。 所有接受 RXR 激动剂治疗的狗在治疗后 6 至 12 个月的随访期间均保持缓解状态。 假设和目标：我们假设人类微腺瘤中正常与腺瘤促肾上腺皮质细胞中 COUP-TFI 的差异表达识别出对类维生素A敏感的肿瘤群体，该群体易受类维生素A诱导的ACTH抑制和细胞凋亡的影响。 这项初步研究的目的是确定库欣病患者接受贝沙罗汀短期治疗的安全性和耐受性，并研究术前五天贝沙罗汀疗程对这些患者的临床、生化和细胞影响。经蝶手术。 主要生化结果指标是每日血浆 ACTH 和皮质醇，以及连续 24 小时尿游离皮质醇水平。 方法：这项试点研究（n = 6 名受试者）将在预定的经蝶手术前 5 天让患者入住我们的普通临床研究中心。 在为期五天的研究中，每个人都将接受 RXR 激动剂贝沙罗汀，剂量为 FDA 批准的 300 毫克/平方米/天。将每 24 小时定期监测急性肾上腺功能不全的临床体征和症状。 将进行 ACTH 和皮质醇的基线和每日两次生化分析。 将在治疗前和治疗最后 24 小时收集 24 小时尿液以检测皮质醇。 实验室安全分析将包括用于监测肝肾功能的系列综合代谢组、用于监测中性粒细胞减少症的全血细胞计数，以及用于监测治疗中可能出现的中枢性甲状腺功能减退症的甲状腺功能研究。