ROSIALITAZONE: NOVEL THERAPY FOR PITUITARY TUMORS (PHAS*

描述(由申请人提供)： 脑垂体瘤很少转移，但会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)是一种参与脂肪和血糖动态平衡的核受体。罗格列酮是一种PPAR-y药物，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的增殖。申请人最近证实PPAR-y在所有被检查的41个脑垂体肿瘤中都有丰富的表达，而在9个尸检获得的正常人类脑垂体中PPAR-y的表达很少。罗格列酮处理促肾上腺皮质激素释放激素阴性和非分泌性肿瘤细胞，使细胞周期停滞于G期，降低S期细胞百分率，诱导肿瘤细胞凋亡，并明显抑制垂体肿瘤激素的产生。他们还观察到，在接受罗格列酮治疗的5名患者中，有4名患者服用罗格列酮控制血糖后尿皮质醇水平降低。 这项第二阶段的临床试验将检验罗格列酮在治疗人类分泌性ACTH(库兴氏病)和非分泌性垂体瘤方面的潜在疗效。根据人类受试者指南，共有45名患者将参与这项研究(研究1和研究2：30名ACTH分泌性脑瘤患者；研究3：15名非分泌性肿瘤患者将纳入研究)。同意的患者将接受详细的基线历史、物理和生化评估，包括特定激素的测量(S)、他们的脑垂体肿瘤产生(例如，ACTH分泌肿瘤的患者将接受ACTH和皮质醇水平的测量)，以及脑垂体肿瘤大小的核磁共振评估。患者将开始使用被批准用于糖尿病的PPAR-y配体罗格列酮(8毫克，每天一次)进行治疗。研究1(库欣病)每周一次，研究2(库欣病)每月进行一次生化和内分泌检查，研究2(库欣病)在基线和6个月时进行放射学检查，研究3(无功能肿瘤)在罗格列酮治疗后基线、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)，即库欣患者的6个月，非分泌性肿瘤患者的12个月。患者的反应将通过随访评估与基线结果的统计比较来确定。完全反应将被定义为库欣患者的尿皮质醇水平正常化，以及非分泌性肿瘤中的脑垂体瘤从基线水平消失。

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.