However, although a higher objective response rate was seen in the sunitinib arm, as was a longer progression free survival time, 13% of the patients died in the sunitinib arm versus 17% in the IFNa arm which was not significant in this analysis. Similarly, sorafenib, another VEGF receptor tyrosine kinase inhibitor, given as second line treatment in a placebo controlled Trichostatin A (TSA) trial, caused a response in 10% of patients but the difference in survival was not statistically significant. There is also biologic rationale for targeting the epidermal growth factor receptor for the treatment of RCC. Still, clinical trials to date have yielded disappointing results. Lapatinib prolonged overall survival and showed a trend towards improved time to progression in a sub group of patients with tumors that overexpressed the EGF receptor.

Gefitinib did not induce objective responses in a small cohort of relapsed RCC but disease control was observed in 53. 8% of patients. Obviously, the present concept of targeted therapy pro vides delayed progression Inhibitors,Modulators,Libraries and extended survival, how ever, responses are mostly partial and of limited Inhibitors,Modulators,Libraries duration. Since aberrant cancer causing pathways address multiple components, we assume that single drug treatment may not be sufficient for long term control of RCC, either due to the development of resistance or due to the develop ment of compensatory feedback loops. In fact, it has recently been observed that blockade of the EGF receptor signaling was compensated by an enhanced VEGF Inhibitors,Modulators,Libraries synthe sis, providing an important survival advantage of VEGF receptor expressing tumor cells.

The cross communication between EGF and VEGF signal ing suggests that associated targeting of both receptor types may be an adequate approach to block RCC growth and progression. Surprisingly, Inhibitors,Modulators,Libraries combined anti EGF and anti VEGF receptor agents seem not be sufficient to achieve a distinct therapeutic benefit in cancer Inhibitors,Modulators,Libraries patients. Thus, Navitoclax additional intra tumoral events correlated to RCC progression should be considered when designing a powerful treatment strategy. Novel data have shown that RCC exhibits constitutive activation of the phosphatidylinositol 3 kinase Akt mammalian target of rapamycin pathway, the downstream effector of VEGF and EGF receptor sign aling. Most importantly, the PI3K Akt mTOR path way is an important mediator of resistance to conventional chemotherapy and to targeted therapy based on EGF or VEGF receptor tyrosine kinase inhibitors. We concluded from these reports that both horizontal and vertical down regulation of growth factor receptor related signaling may be required to optimize the current protocol of tumor targeting.