The ultimate goal of our program is to discover new targets for vasculature disrupting therapy of cancer, either as such or as sensitizers to the existing vasculature disrupting treatments with Tumor Necrosis Factor or combretastatins. We already could demonstrate that TNF exerts these effects through interaction with the TNFR1 on endothelial cells and will now elucidate the downstream mechanisms to find new targets, selectively mimicking the antitumor effect of TNF. We also could demonstrate that addition of PI3K inhibitors or (alpha)Gal Cer can reduce the therapeutic dose of TNF tenfold and bring it close to the estimated tolerated level. Wel will now further develop these approaches.