One area of focus is on developing novel therapeutic approaches to inhibit new blood vessel formation (angiogenesis) in malignant glioma tumors (eg., glioblastomas), both adult and pediatric. For example, we have recently shown that the death receptor TNF-R1 is required for the anti-angiogenic effect of thrombospondin, and that TNF-R1 and its ligand TNFalpha are upregulated on the new blood vessels in these tumors and correlate with a better survival. Furthermore, our studies on the regulation of TNF-R1 on these blood vessels has identified which integrin (cell adhesion) receptors negatively or positively regulate the pro-death signal of TNF-R1, and when taken together with known integrin receptor expression data suggest that therapeutically activating TNF-R1 would likely be beneficial as part of a combination therapy.
Another area of focus is to identify the key pro-survival proteins that are upregulated in malignant glioma tumors, as such proteins could be novel therapeutic targets. For example, we recently reported that a large protein known as FIP200 is upregulated on the new blood vessels in glioblastoma tumors and identified a novel mechanism for its pro-survival function (inhibition of Pyk2 activation). We are currently determining the key regulators of FIP200 expression in endothelial cells and cancer cells, and are creating peptides from regions of FIP200 that can be used as dominant negative constructs. These peptides will be used for the creation of monoclonal antibodies to inhibit FIP200 pro-survival function and will be useful for research and therapeutic purposes.