ROSIALITAZONE: NOVEL THERAPY FOR PITUITARY TUMORS (PHAS*

描述（由申请人提供）： 垂体瘤很少转移，但引起相当大的发病率和死亡率。 过氧化物酶体增殖物激活受体-γ（PPAR-y）是参与脂肪和葡萄糖稳态的核受体。 罗格列酮是一种PPAR-γ配体，已被批准用于糖尿病的治疗。PPAR-y配体抑制前列腺癌和乳腺癌细胞增殖。 申请人最近证明，与9个尸检来源的正常人垂体中的最小PPAR-表达相比，在所有41个检查的垂体肿瘤中有丰富的PPAR-γ表达。 罗格列酮处理ACTH-和非分泌肿瘤细胞导致G细胞周期停滞，减少S期细胞的百分比，诱导肿瘤细胞凋亡，并显著抑制垂体肿瘤激素的产生。 他们还观察到，罗格列酮治疗血糖控制导致4/5例罗格列酮治疗患者尿皮质醇水平降低。 这项2期临床试验将检查罗格列酮治疗人ACTH分泌型（库欣病）和非分泌型垂体瘤的潜在疗效。 根据人类受试者的指南，总共45名患者将参与本研究（研究1和2：30名ACTH分泌型垂体瘤患者;研究3：将招募15名非分泌型肿瘤患者）。 患者将接受详细的基线历史，身体和生化评估，包括测量特定激素，他们的垂体瘤产生（例如，ACTH分泌肿瘤的患者将测量其ACTH和皮质醇水平），并对垂体肿瘤大小进行MRI评估。 患者将开始用批准用于糖尿病的PPAR-y配体罗格列酮（8 mg口服，每天一次）治疗。 在研究I（库欣）和研究2（库欣）中，将每周重新评价一次生化和内分泌检查，并在基线时和研究2（库欣）中6个月时以及研究3（无功能肿瘤）中基线、6个月和12个月时进行放射学检查。 在没有副作用或其他禁忌症的情况下，罗格列酮治疗将持续6周（研究1）或库欣患者6个月，非分泌性肿瘤患者12个月。 将通过随访评估与基线结果的统计学比较确定患者应答。 完全缓解将定义为库欣患者的尿皮质醇水平正常化，非分泌性肿瘤中的垂体瘤从基线消失。

DESCRIPTION (provided by applicant): Pituitary tumors rarely metastasize, but cause considerable morbidity and mortality. The peroxisome proliferator activating receptor-gamma (PPAR-y) is a nuclear receptor involved in fat and glucose homeostasis. Rosiglitazone, a PPAR-y ilgand, is approved for the management of diabetes mellitus. PPAR-y ligands inhibit prostate and breast cancer cell proliferation. The applicant recently demonstrated abundant PPAR-y expression in all of 41 pituitary tumors examined, in comparison to minimal PPAR- expression in 9 autopsy-derived normal human pituitaries. Rosiglitazone treatment of ACTH-, and non- secreting tumor cells led to G cell cycle arrest, decreased the percentage of S-phase cells, induced tumor cell apoptosis, and markedly inhibited pituitary tumor hormone production. They also observed that rosiglitazone treatment for glycemic control led to reduced urine cortisol levels in 4 of 5 rosiglitazone treated patients. This Phase 2 clinical trial will examine the potential therapeutic efficacy of rosiglitazone in treatment of human ACTH-secreting (Cushing's disease), and non-secreting pituitary tumors. In accordance with human subjects' guidelines, a total of 45 patients will participate in the study (Study 1 and 2: 30 patients with ACTH-secreting pituitary tumors; study 3: 15 patients with non-secreting tumors will be recruited). Consenting patients will undergo a detailed baseline historical, physical and biochemical evaluation, including measurement of the specific hormone(s), their pituitary tumor produces (e.g., patients with ACTH-secreting tumors will have their ACTH and cortisol levels measured), and a MRI assessment of the pituitary tumor size. Patients will commence treatment with PPAR-y ligand rosiglitazone, (8 mg by mouth, once per day) as approved for use in diabetes mellitus. Biochemical and endocrine examination will be re-evaluated weekly in study I (Cushing's) and monthly in study 2 (Cushing's), and radiological examination at baseline and at 6 months in study 2 (Cushing's), and baseline, 6, and 12 months in study 3 (non-functioning tumor) after rosiglitazone treatment. In the absence of side-effects or other contraindications, rosiglitazone therapy will continue for a total period of 6 weeks (study 1) or 6 months in the Cushing's patients and 12 months in patients with non-secreting tumors. Patient response will be determined by a statistical comparison of the follow-up assessments with baseline result. A complete response will be defined as normalization of urinary cortisol levels in the Cushing's patients, and disappearance of pituitary tumors in the non-secreting tumors from baseline.