Utility of Rapamycin for the Treatment of Renal Angiomy*

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存在，这在很大程度上是由于遗传事件的复杂性导致细胞生长不调节。结节性硬化症是一种遗传性癌症综合征，与多器官错构瘤的形成有关，包括肾脏的血管平滑肌脂肪瘤，由编码相互作用蛋白、结节蛋白或错构瘤的基因位点的失活突变引起。最近的一些研究阐明了tuberin/错构体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（Rapamycin）是一种经FDA批准的免疫抑制剂，用于预防肾移植排斥反应，它通过与Akt下游一种名为哺乳动物雷帕霉素靶蛋白（mTOR）的蛋白质结合，模仿tuberin/错构体复合物的功能，抑制控制细胞周期和蛋白质翻译的远端元件的磷酸化。雷帕霉素已被证明能特异性地抑制来自人类、啮齿动物和苍蝇的tuberin和错构体缺陷细胞的生长，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结节性硬化症复合体研究会议上的一致意见是，在TSC中使用雷帕霉素的临床前证据足够令人信服，可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例血管平滑肌脂肪瘤患者来实现，这些患者要么是结节性硬化症患者，要么是与结节性硬化症基因突变相关的散发性淋巴管平滑肌瘤病患者，使用剂量调整的雷帕霉素治疗一年。肾血管平滑肌脂肪瘤的大小、数量、体积和组织组成将通过治疗前、2个月、4个月和每6个月进行肾脏MRI扫描来监测。TSC的其他表现，包括脑、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。产生效果的最小雷帕霉素剂量，定义为血管平滑肌脂肪瘤体积减少10%以上，将从导致亚免疫抑制的剂量开始滴定到产生低至中度免疫抑制范围的剂量。根据NCI共同毒性标准定义的毒性将被仔细监测、报告并迅速处理。本研究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.