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 therapeuticly 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 kown 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.
One area of focus is on developing novel approaches to block new blood vessel formation (angiogenesis) in malignant glioma tumors (eg., glioblastoma), both adult and pediatric. This is a major problem as these tumors are notorious for the development of an extensive network of new blood vessels that are thought to be key for the growth and spread of the tumor. We recently showed that a pro-death molecule (TNF-R1) is highly expressed on these new blood vessels, probably as part of the brain anti-tumor response, and we are currently turning on the pro-death signal of TNF-R1 on the new blood vessels in these tumors as part of a therapeutic approach.
Another area of focus is to identify the key molecules that promote life or survival in malignant glioma tumors, such molecules could be novel therapeutic targets. Cancer cells frequently show increased expression of pro-survival molecules. We are interested in one such molecule called FIP200 that promotes survival of cells in glioblastoma tumors. We are creating small pieces of the FIP200 molecule that can be used to interfere with FIP200 pro-survival function, and they will be tested for anti-tumor therapeutic effect.
Wang D, Olman MA, Stewart JE Jr.,Tipps R, Huang P, Sanders PW, Toline E, Prayson R, Lee J, Wei Rl, Palmer CA, Gillespie GY, Liu WM, Pieper R, Guan J-L, and Gladson CL. Downregulation of FIP200 Induces Apoptosis of Glioblastoma and Endothelial Cells by Enhancing Pyk2 Activity. PLoS ONE, 2011;6(5):e19629.doi:10.1371/journal.pone.0019629.
Huang P, Rani MRS, Ahluwalia M, Bae E, Prayson RA, Weil RJ, Nowacki AS, Hedayat H, Sloan AE, Lathia JD, Rich JN, Tipps R, and Gladson CL, Endothelial TNF- R1 Generates a Pro-apoptotic Signal Inhibited by Integrin α6β1 in Glioblastoma, Cancer Research 2012;72(6):1428-1437.
Lathia J, Gallagher J, Hall P, Li M, Levy E, Venere M, Rani MRS, Huang P, Cheng L, McLendon R, Sloan A, Bao S, Gladson CL, Bredel M, Hjelmeland A, and Rich J. Perivascular Niche Matrix Instructs Brain Tumor Hierarchies. Annuals of Neurology, 2012.