Utility of Rapamycin for the Treatment of Renal Angiomy*

雷帕霉素治疗肾血管瘤的效用*

基本信息

批准号：
6795885
负责人：
JOHN J BISSLER
金额：
$ 27.43万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2006-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Targeted molecular therapy is the ultimate objective for the management of neoplasia, but only a few examples exist in practice, due in large part to the complexity of genetic events that result in unregulated cell growth. Tuberous sclerosis is an inherited cancer syndrome associated with the formation of hamartomas in multiple organs, including angiomyolipomas in the kidney, caused by well-characterized inactivating mutations at genetic loci that encode the interacting proteins, tuberin or hamartin. Elegant studies have recently elucidated the pivotal role of the tuberin/hamartin complex in the checkpoint control of the Akt signaling pathway that regulates cell growth and division. Rapamycin, an FDA immunosuppressive approved drug used to prevent renal transplant rejection, mimics the function of the tuberin/hamartin complex by binding to a protein downstream of Akt called mammalian target of rapamycin (mTOR) and inhibiting the phosphorylation of more distal elements that control cell cycle and protein translation. Rapamycin has been shown to specifically inhibit the growth of tuberin and hamartin deficient cells from humans, rodents and flies, and to produce tumor regression in rats and mice. The consensus opinion of the recent Tuberous Sclerosis Complex Research conference in Chantilly, Virginia was that the preclinical evidence for the use of rapamycin in TSC was sufficiently compelling to warrant a human trial. The objective of the current study is to determine if rapamycin reduces the volume of angiomyolipomas. This goal will be accomplished by treatment of thirty patients with angiomyolipomas, either in the setting of tuberous sclerosis, or a related disease associated with mutations in tuberous sclerosis genes called sporadic lymphangioleiomyomatosis, with dose-adjusted rapamycin for a period of one year. The size, number, volume and tissue composition of renal angiomyolipomas will be monitored by MRI scans of the kidney, performed prior to treatment, at two months, four months, and every six months. Other manifestations of TSC, including brain, skin and lung lesions, will also be monitored with appropriate clinical, functional and imaging techniques. The minimal rapamycin dose that produces an effect, defined as a greater than 10% decrease in angiomyolipoma volume, will be titrated beginning with doses that result in subimmunosuppressive serum levels to those that produce levels in the low to modestly immunosuppressive range. Toxicities, as defined by the NCI common toxicities criteria, will be carefully monitored, reported, and expeditiously addressed. Successful completion of the aim of this study will help to establish tuberous sclerosis as a valuable model for targeted molecular therapy for neoplasia.

描述（由申请人提供）：靶向分子治疗是肿瘤治疗的最终目标，但在实践中只有少数例子，这在很大程度上是由于导致细胞生长失控的遗传事件的复杂性。结节性硬化症是一种遗传性癌症综合征，与多个器官中错构瘤的形成相关，包括肾脏中的血管平滑肌脂肪瘤，这是由编码相互作用蛋白、马铃薯蛋白或错构蛋白的基因位点的明确失活突变引起的。最近的优雅研究阐明了马铃薯蛋白/错构瘤蛋白复合物在调节细胞生长和分裂的 Akt 信号通路的检查点控制中的关键作用。雷帕霉素是一种 FDA 批准的免疫抑制药物，用于预防肾移植排斥，通过与 Akt 下游的一种称为哺乳动物雷帕霉素靶蛋白 (mTOR) 的蛋白质结合，并抑制控制细胞的更远端元件的磷酸化，从而模拟马铃薯球蛋白/错构蛋白复合物的功能循环和蛋白质翻译。雷帕霉素已被证明可以特异性抑制人类、啮齿动物和果蝇的马铃薯球蛋白和错构蛋白缺陷细胞的生长，并使大鼠和小鼠的肿瘤消退。最近在弗吉尼亚州尚蒂伊举行的结节性硬化症综合研究会议达成的共识是，在结节性硬化症中使用雷帕霉素的临床前证据足以令人信服，足以保证进行人体试验。当前研究的目的是确定雷帕霉素是否可以减少血管平滑肌脂肪瘤的体积。这一目标将通过对 30 名患有血管平滑肌脂肪瘤的患者进行为期一年的剂量调整雷帕霉素治疗来实现，这些患者要么是结节性硬化症，要么是与结节性硬化症基因突变相关的疾病（称为散发性淋巴管平滑肌瘤病）。将通过在治疗前、两个月、四个月和每六个月进行的肾脏 MRI 扫描来监测肾血管平滑肌脂肪瘤的大小、数量、体积和组织成分。 TSC 的其他表现，包括脑部、皮肤和肺部病变，也将通过适当的临床、功能和成像技术进行监测。产生作用的最小雷帕霉素剂量（定义为血管平滑肌脂肪瘤体积减少超过 10%）将从导致亚免疫抑制血清水平的剂量开始滴定至产生低至中等免疫抑制范围水平的剂量。 NCI 通用毒性标准定义的毒性将受到仔细监测、报告并迅速解决。本研究目标的成功完成将有助于建立结节性硬化症作为肿瘤靶向分子治疗的有价值的模型。