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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 背景：Cushing的疾病是指由产生垂体肿瘤的肾上腺皮质激素（ACTH）引起的糖皮质激素EXCESS，占所有垂体肿瘤的10-15％。在诊断时，大多数皮质营养肿瘤是MicroadeNomas，这些肿瘤的准确手术和组织学鉴定可能具有挑战性。 ACTH是通过前体促蛋白质素（POMC）在前垂体内的皮质营养细胞中产生的。在生理和病理状况中，POMC的启动子受多种转录因子的调节，包括AP-1和Nurr77。维甲酸已显示可通过破坏Nurr77转录活性来抑制皮质营养肿瘤细胞培养中POMC启动子的激活。孤儿核受体的表达称为鸡卵蛋白上游启动子转录因子I（coup-TFI）拮抗视黄酸信号传导，据报道在正常的皮质营养细胞中存在，但缺乏在组织培养研究中的腺瘤性皮质营养细胞。 通过对34种人类皮质营养肿瘤的回顾性分析，我们表明100％不可见的MICOXENOMAS始终缺乏COUP-TFI，或者通过术前MRI测量了小于5毫米。 总共有85％的所有研究肿瘤都没有coup-TFI。 基于来自大鼠和人皮质营养肿瘤的体外数据，缺乏coup-TFI的细胞通过Nurr77介导的细胞凋亡容易受到类维生素性诱导的细胞死亡的影响，这种作用被Coup-TFI基因转染逆转。 2006年，Castillo等。发表了为期六个月的试验的结果，该试验将库欣疾病的44只狗随机分配给RXR激动剂（9-cis视黄酸）或酮康唑。 RXR激动剂疗法的表现优于所有终点的酮康唑，导致100％完成研究的受试者的ACTH和皮质醇水平正常化，并提高了发病率和死亡率。 在治疗后6到12个月的随访期间，所有用RXR激动剂治疗的狗仍处于缓解状态。 假设和目标：我们假设人类MicroadeNomas中的coup-TFI在正常与腺​​瘤皮质营养细胞中的差异表达鉴定出类维生素性敏感的肿瘤群体，这容易受到类视黄素诱导的ACTH抑制和凋亡的影响。 这项试验研究的目的是在库欣氏病患者中建立短期治疗对北卡罗烯的安全性和耐受性，并研究这些患者在这些患者进行临床疗程五天培养基疗程的临床，生化和细胞作用。 主要的生化结果指标将是昼夜血浆ACTH和皮质醇，以及连续24小时无尿的皮质醇水平。 方法：这项试验研究（n = 6个受试者）将在预定的跨体手术前5天涉及进入我们的一般临床研究中心的住院。 在研究的五天内，每个人将以FDA认可的300 mg/m2/天的剂量获得RXR-aghtim bexarotene。急性肾上腺功能不全的临床体征和症状将在每个24小时内常规监测。 将对ACTH和皮质醇进行两次基线和两次生化分析。 在治疗的最后24小时，将获得24小时的皮质醇尿液收集。 实验室安全分析将包括串行综合代谢面板，以监测肝脏和肾脏功能，完全血液计数以监测中性粒细胞减少症以及甲状腺功能研究，以监测可以通过治疗发展的中枢性甲状腺功能减退症。