RAD001 THERAPY OF ANGIOMYOLIPOMATA IN PATIENTS WITH TSC

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。靶向分子治疗是恶性肿瘤治疗的最终目标，但目前只有少数几个例子，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。结节性硬化症是一种遗传性癌症综合征，与多个器官错构瘤的形成有关，包括肾脏的血管肌脂肪瘤，由编码相互作用蛋白Tuberin或Hamartin的遗传位点的失活突变引起。最近的研究阐明了tuberin/hamartin复合体在控制Akt信号通路中的关键作用，Akt信号通路调节细胞的生长和分裂。本研究的目的是确定mTOR抑制剂是否能减少血管肌脂肪瘤的体积。这一目标将通过治疗30名血管肌肉脂肪瘤患者来实现，这些患者要么是结节性硬化症，要么是一种与结节性硬化症基因突变相关的疾病，称为散发性淋巴管肌瘤病，用剂量调整后的RAD001治疗一年。肾脏血管肌脂肪瘤的大小、数量、体积和组织组成将通过肾脏的MRI或CT扫描进行监测，这些扫描在治疗前、治疗后6个月、1年和2年进行。RAD001的剂量将被修改，以确定是否存在导致细胞凋亡的阈值，而不仅仅是细胞体积的变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Targeted molecular therapy is the ultimate objective for the management of malignancy, but only a few examples exist, 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. Recent studies have elucidated the pivotal role of the tuberin/hamartin complex in controlling the Akt signaling pathway that regulates cell growth and division. The objective of this study is to determine if an mTOR inhibitor 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 RAD001 for a period of one year. The size, number, volume and tissue composition of renal angiomyolipomas will be monitored by MRI or CT scans of the kidney, performed prior to treatment, at six months, one and two years. The dose of RAD 001 will be modified to see if there is a threshold does that leads to apoptosis versus a mere cell volume change.