PREOPERATIVE BEXAROTENE TREATMENT FOR CUSHING'S DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 背景资料：库欣氏病是由产生促肾上腺皮质激素（ACTH）的垂体瘤引起的糖皮质激素缺乏的病症，其占所有垂体瘤的10-15%。大多数促肾上腺皮质激素细胞肿瘤在诊断时是微腺瘤，这些肿瘤的准确手术和组织学鉴定可能具有挑战性。促肾上腺皮质激素通过前体阿黑皮素原（POMC）在垂体前叶内的促肾上腺皮质激素细胞中产生。在生理和病理条件下，POMC的启动子受多种转录因子调节，包括AP-1和Nurr 77。已显示视黄酸通过破坏Nurr 77转录活性来抑制促肾上腺皮质激素肿瘤细胞培养物中POMC启动子的活化。孤儿核受体鸡卵清蛋白上游启动子转录因子I（COUP-TFI）的表达拮抗视黄酸信号，并已被报道存在于正常的促肾上腺皮质激素细胞，但缺乏腺瘤性促肾上腺皮质激素细胞在组织培养研究。 通过对34例促肾上腺皮质激素细胞肿瘤的回顾性分析，我们证明了术前MRI检查不可见或测量小于5 mm的微腺瘤中100%持续缺乏COUP-TFI。 总的来说，85%的肿瘤研究显示COUP-TFI的缺乏。 基于大鼠和人促肾上腺皮质激素细胞肿瘤的体外数据，缺乏COUP-TFI的细胞容易通过Nurr 77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，COUP-TFI基因转染可以逆转这种作用。 2006年，Castillo等人发表了一项为期6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激动剂治疗在所有终点方面均优于酮康唑，导致100%完成研究的受试者的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激动剂治疗的犬在治疗后6至12个月随访期间均保持缓解。 假设和目标：我们假设COUP-TFI在人类微腺瘤中正常与腺瘤性促肾上腺皮质激素细胞中的差异表达鉴定了易受维甲酸诱导的ACTH抑制和凋亡的维甲酸敏感性肿瘤群体。 本初步研究的目的是确定库欣病患者短期使用贝沙罗汀治疗的安全性和耐受性，并研究这些患者在接受经蝶手术前术前5天贝沙罗汀治疗的临床、生化和细胞效应。 主要的生化结果测量将是昼夜血浆ACTH和皮质醇，以及连续24小时尿游离皮质醇水平。 研究方法：本项初步研究（n = 6例受试者）将涉及在计划的经蝶窦手术前5天住院至我们的综合临床研究中心。 在研究的五天期间，每个个体将以FDA批准的剂量300 mg/m2/天接受RXR激动剂贝沙罗汀。将在每24小时内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。 24-将在治疗前和治疗的最后24小时内采集用于皮质醇的1小时尿液。 实验室安全性分析将包括监测肝肾功能的系列综合代谢检查、监测中性粒细胞减少的全血细胞计数以及监测治疗可能发生的中枢性甲状腺功能减退症的甲状腺功能研究。

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.