It has been shown that human leukemic cells trea ted with L asparaginase have reduced levels of the mTOR pathways targets p70 S6 kinase and 4E binding protein 1. Furthermore, there are tissue specific changes in mTOR pathway inhibition and cellular stress response signals in mice treated with L asparaginase. Due to its inhibitory effects Ganetespib OSA on growth of malignant cells and mTOR pathway activity in some tissues, L asparaginase may be useful in treating TSC related tumors. Vascular endothelial growth factor signaling is thought to play an important role in the pathogenesis of TSC and LAM. Inhibitors,Modulators,Libraries Since the brain, skin, and kidney tumors associated with TSC are vascular and TSC2 loss is associated with increased levels of HIF and VEGF in cultured cells, VEGF is a potential target for TSC treatment.
Furthermore, recent studies have shown that serum VEGF D levels are elevated in patients with sporadic or TSC associated LAM compared with healthy controls Inhibitors,Modulators,Libraries and patients with other pulmonary ailments. The importance of VEGF signaling in the pathogenesis of TSC suggests that VEGF inhibitors as single agents or in combination with mTOR inhibitors may provide a promising treatment. Sorafenib is an oral multi targeted kinase inhibitor that blocks vascular endothelial growth factor receptor 1, VEGFR 2, VEGFR 3, the RAF Mek Erk pathway, PDGFR, FLT 3, and C KIT. It is FDA approved for the treatment of advanced renal cell and hepatocellular carcinoma. We have previously shown that the combination of sorafenib plus rapamycin is more effective than single agents in TSC tumor preclinical studies, but have not tested other VEGF signaling path way inhibitors.
Sunitinib is a receptor tyrosine kinase inhibitor that tar gets both VEGF R and platelet derived growth factor receptor. Sunitinib has been shown to increase response and survival in patients Inhibitors,Modulators,Libraries with meta Inhibitors,Modulators,Libraries static renal cell carcinoma and is also approved for the treatment of gastrointestinal stromal tumors. Bevacizumab is a recombinant humanized monoclonal antibody that binds all human VEGF isoforms and is approved for the treatment of colon, breast, non small cell lung cancer, and glioblastoma and also pro longs the time to progression of disease in metastatic RCC. The inhibitory effects of sunitinib and bev acizumab Inhibitors,Modulators,Libraries on VEGF signaling suggest that they may be useful in the treatment of TSC related tumors.
Recent studies have shown that the TSC1 TSC2 com plex may be important for microtubule dependent selleck catalog pro tein transport because microtubule distribution and protein transport are disrupted in cells lacking Tsc1 or Tsc2. This raises the possibility that microtubule inhibitors may have useful anti tumor activity for TSC related tumors. Vincristine is an anti neoplastic micro tubule inhibitor that binds tubulin dimers to arrest rapidly dividing cells in metaphase. It is used in combination with other drugs in the treatment of lym phoma and leukemia.