RAD001, the 40 O derivative of rapamycin, blocks proliferation of several tumor cell lines in vitro. No detailed analysis has been carried out on RCC cell lines. However, clinical trials confirm the rele vance of targeting the mTOR pathway in RCC. RAD001 has recently been shown to exhibit a partial response and somehow stable disease in a phase II trial of patients with RCC. Progression free survival was 11. 2 months. Another phase II trial evaluating RAD001 was presented at ASCO 2008 and shows encour aging anti tumor activity in RCC patients which have had prior exposure to sorafenib or sunitinib. Finally, treatment with RAD001 prolonged progression free sur vival relative to placebo in patients with metastatic RCC in a phase III study. We present evidence that RAD001 significantly influences RCC adhesion and growth behaviour.

RAD001 had a Inhibitors,Modulators,Libraries dis tinct impact on the suppression of cellular S phase frac tion and modification of cell cycle protein expression. Remarkably, RAD001s effects on cell cycle proteins did not always parallel the characteristics of AEE788. Notably, cyclin D1 were found Inhibitors,Modulators,Libraries to be reduced by AEE788 in syn chronized Caki 1 cells but remained unchanged in the presence of RAD001 at a particular time point. It is not clear if cyclin D1 is incompletely targeted by RAD001 W or if RAD001 acts in a differ ent manner than AEE788. Studies on malignant glioblas toma cells revealed both compounds to affect cellular proliferation in different ways. Therefore, non over lapping mechanisms should be considered when inter preting our data.

This is an important issue, as some targeted therapies require the cell to enter specific cell cycle points to induce therapeutic effects. As the most important message, simultaneous use of both AEE788 and RAD001 offered a distinct combinatorial benefit and thus may provide a therapeutic advantage over either agent as monotherapy for RCC treatment. This is highly Inhibitors,Modulators,Libraries relevant, since single agents rarely induced com plete responses in clinical trials, presumably due to com pensatory cross talk among receptors within a signaling network as well as with heterologous receptor systems in Inhibitors,Modulators,Libraries RCC cells. Combinations of targeted agents could improve limited therapeutic efficacy and overcome resist ance that might develop under single agent therapy. At the present, two different concepts of combination tar geted therapy for RCC are discussed.

Horizontal block ade is aimed to concurrently target numerous molecules involved in RCC proliferation and dissemination. The other popular Inhibitors,Modulators,Libraries concept of vertical blockade is aimed to target the same pathway at two or more different levels. Concerning the latter, inhibitor Ganetespib synergistic effects were seen in sev eral tumor cell lines when both mTOR and EGF receptor inhibitors were administrated in combination. Recent data suggest that combining mTOR with VEGF receptor inhibitors may have clinical potential to enhance survival of cancer patients.