This in turn causes increased cell growth, pro liferation, Ganetespib OSA and survival. Rapamycin, an FDA approved mTOR inhibitor for immunosup pression following kidney transplantation, has been shown to ameliorate disregulated mTOR signaling in cells that lack normal hamartin or tuberin. Furthermore, rapamycin and some of its analogs have successfully treated TSC related tumors, seizures, and cognitive defects in relevant rodent disease models. Rapamycin treatment was also effective in reducing TSC related kidney angiomyol ipomas with tolerable side effects in human clinical trials, and tumor regression was observed in a case series of TSC patients with brain tumors who were treated with off label rapamycin. There are several rapamycin analogs that are also under investigation as anti tumor agents.

One of these, CCI 779, has been FDA approved Inhibitors,Modulators,Libraries for the treatment of advanced renal cell carcinoma. While rapamycin effectively reduces the size of many TSC associated tumors in humans, tumor regression does not occur in all cases and tumor regrowth is generally observed with the cessation of treatment. Although the response results in early human trials Inhibitors,Modulators,Libraries are encouraging, it is possible that a longer term use of rapamycin may be more effective. Identification of other active drugs is also of interest to improve the response rate and or durability Inhibitors,Modulators,Libraries of response. There is some evidence that other drug classes, including inhibitors of VEGF signaling, interferon gamma, HMG CoA reductase inhibi tors, and MMP inhibitors may be useful in treating TSC and or LAM.

There is increasing evidence that VEGF signaling plays an important role in the pathogenesis of TSC and LAM. Brain, kidney and skin tumors associated with TSC are known to be vascular, and TSC2 loss is associated Inhibitors,Modulators,Libraries with elevated levels of HIF and VEGF in cultured cells. Furthermore, in recent biomarker studies of the VEGF family, serum levels of VEGF D were found to be significantly elevated in patients with sporadic or TSC associated LAM as compared with healthy controls and patients with other pulmonary illnesses. The importance of VEGF signaling in TSC and LAM suggests that combination therapies that aim to inhibit mTOR sig naling along with disrupting VEGF signaling may be more successful than single agents. Sorafenib is an oral multi targeted kinase inhibitor that inhibits VEGFR 1, VEGFR 2, and VEGFR 3 Inhibitors,Modulators,Libraries in addition to the Raf Mek Erk pathway, PDGFR, FLT 3, and c KIT. It is also FDA approved selleck products for the treatment of advanced renal cell carcinoma and advanced hepatocellular carcinoma. As a result of its inhibitory effects on angiogenic and tumorigenic molecu lar targets, sorafenib may be useful for treating TSC related tumors.