RAD001 THERAPY OF ANGIOMYOLIPOMATA IN PATIENTS WITH TSC

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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.