Rapamycin for the Treatment of Renal Angiomyolipomas

描述（由申请人提供）：靶向分子治疗是肿瘤管理的最终目标，但在实践中仅存在少数实例，这在很大程度上是由于导致细胞生长不受调控的遗传事件的复杂性。硬化症是一种遗传性癌症综合征，与多器官错构瘤（包括肾脏血管平滑肌脂肪瘤）的形成相关，由编码相互作用蛋白质（块茎蛋白或错构蛋白）的遗传基因座的充分表征的失活突变引起。优雅的研究最近已经阐明了块茎蛋白/错构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FDA批准的用于预防肾移植排斥反应的免疫抑制药物，其通过结合Akt下游的称为雷帕霉素哺乳动物靶标（mTOR）的蛋白质并抑制控制细胞周期和蛋白质翻译的更远端元件的磷酸化来模拟块茎蛋白/错构蛋白复合物的功能。雷帕霉素已显示特异性抑制来自人类、啮齿动物和苍蝇的块茎蛋白和错构蛋白缺陷细胞的生长，并在大鼠和小鼠中产生肿瘤消退。最近在弗吉尼亚州尚蒂伊举行的多发性硬化症研究会议的共识是，雷帕霉素在TSC中使用的临床前证据足以令人信服，足以保证人体试验。本研究的目的是确定雷帕霉素是否能减少血管平滑肌脂肪瘤的体积。这一目标将通过治疗30例患有血管平滑肌脂肪瘤的患者来实现，无论是在结节性硬化症的背景下，还是与结节性硬化症基因突变相关的称为散发性淋巴管平滑肌瘤病的相关疾病中，使用剂量调整的雷帕霉素治疗一年。将通过在治疗前、2个月、4个月和每6个月进行的肾脏MRI扫描监测肾血管平滑肌脂肪瘤的大小、数量、体积和组织组成。还将采用适当的临床、功能和成像技术监测TSC的其他表现，包括脑、皮肤和肺部病变。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大于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度免疫抑制范围内水平的剂量。将仔细监测、报告并迅速解决NCI常见毒性标准定义的毒性。本研究目的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。

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.