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.
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