The inhibitory function of the tuberin hamartin complex results from tuberins GTP ase activ ity on Rheb, which directly regulates mTOR kinase activity. thenthereby When conditions are unfavorable for cell growth and the TSC1 TSC2 complex is functioning properly, Rheb GTP is converted to the GDP form and mTOR kinase activity is decreased. When mutations occur in TSC1 or TSC2, the hamartin tuberin complex is nonfunctional, Rheb GTP is favored, and mTOR kinase is constitutively activated causing hyperphosphor ylation of the downstream effectors resulting in increased protein translation, cell growth, proliferation, and survival. Several TSC genotype phenotype studies show that TSC2 disease is both more common and more severe than TSC1 disease.

The Tsc2 mouse is a good model for TSC related Inhibitors,Modulators,Libraries kidney disease because it is genetically similar to the majority of those with TSC, it develops age related kidney tumors, and the mTOR pathway defect that occurs in the kidney tumors of Tsc2 mice is similar to that observed in human TSC related tumors. Nude mice bearing subcutaneous Tsc2 tumors derived from mouse Inhibitors,Modulators,Libraries embryo fibroblasts are another useful animal model for TSC related tumors. The Tsc2 subcutaneous tumor model is a good generic model for TSC related tumors because loss of heterozygosity has been found in many TSC related kidney and brain tumors. Rapamycin is a macrolide antibiotic that acts to inhibit the mTOR pathway and is FDA approved for use as an immunosuppressant following organ transplantation. More recently, two rapamycin analogs have been approved for the treat ment of renal cell carcinoma.

Rapamycin have been shown to restore disregulated mTOR signaling in Inhibitors,Modulators,Libraries cells with Inhibitors,Modulators,Libraries abnormal TSC1 and or TSC2 and to successfully treat kidney lesions in the Tsc2 mouse model along with other rodent models. Furthermore, in early clinical trials evalu ating the utility of rapamycin for the treatment of kid ney angiomyolipomas associated with TSC and or LAM, partial tumor regression has been observed in the majority of cases. Because responses are incomplete, not all tumors respond to drug therapy, and patients experi ence kidney angiomyolipoma regrowth after cessation of treatment, further studies are needed to evaluate longer duration mTOR inhibitor treatment and also to identify other active drugs.

There is evidence that other drug classes, such as those that alter amino acid metabolism, inhibitors of VEGF signaling, and microtubule inhibitors may be use ful in treating TSC. The presence or absence of amino acids is an important regulator Inhibitors,Modulators,Libraries of mTOR signaling. L Asparaginase is an enzyme that catalyzes the hydroly sis of L asparagine to L aspartic acid and is used as part of the curative combination chemotherapy regimen for the treatment of acute lymphoblastic selleck MEK162 leukemia.