Encouraging clinical studies show that agents targeting

Encouraging clinical studies show that agents targeting selleck products VEGF and tumor angiogenesis Inhibitors,Modulators,Libraries significantly prolong pro gression free survival in patients with RCC. Among those agents, sorafenib has been approved for the treat ment of advanced RCC. Initially identified as a Raf kinase inhibitor, sorafenib also blocks the kinase activ ities of several receptors including VEGF receptor 1, 2, 3 and platelet derived growth factor receptor beta. Sorafenib exhibits antitumor activity in several experi mental models of renal cancer, primarily by inhibiting angiogenesis. In addition to sorafenib, allosteric inhibitors of the mammalian target of rapamycin have also been approved for the treatment of advanced RCC. The rationale of targeting mTOR in RCC is related to the observation that mTOR regulates the expression of HIF 1a.

Two such inhibitors, temsirolimus Inhibitors,Modulators,Libraries and everolimus, have significant activity in patients with advanced RCC and prolong the progres sion Inhibitors,Modulators,Libraries free survival. However, the responses are short lived and most of the patients finally develop resistance. These limited benefits observed in clinical trials are partially explained by experimental evidences where treatment of cells with rapamycin, or its analogs temsirolimus and everolimus, activates the PI3K Akt signaling pathway by the removal of a negative feed back loop. In turn, the activation of PI3K Akt results in the activation of proliferative and pro survi val signals that counteract the anticancer efficacy of rapamycin. Furthermore, mTOR exists in two different complexes, mTORC1 and mTORC2. While mTORC1 is sensitive to rapamycin, mTORC2 is not.

Finally, not all the functions of mTORC1 are targeted by rapa mycin. To overcome these limitations, a new gen eration of agents targeting the ATP binding Inhibitors,Modulators,Libraries domain of mTOR and inhibiting both mTORC1 and mTORC2 has been developed. Among these agents, NVP BEZ235 is a dual PI3K mTOR inhibitor currently in clinical development. The antitumor efficacy of NVP Inhibitors,Modulators,Libraries BEZ235 has been demonstrated in numerous http://www.selleckchem.com/products/BAY-73-4506.html pre clinical models, including RCC where its antic ancer efficacy is shown to be superior to rapamycin. Interestingly, NVP BEZ235 has little effect on tumor angiogenesis in RCC suggesting that its antitu mor efficacy may be potentiated in combination with anti angiogenic therapy. Despite having improved the clinical outcome of patients with RCC, targeted therapies are not associated with long lasting responses. Consequently, there is a strong need to develop new therapeutic strategies for the treatment of RCC. In this report, we have analyzed the effects of NVP BEZ235 in combination with the anti angiogenic compound sorafenib on renal cancer cell lines in vitro and on renal tumor xenografts in vivo.

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