This is a Feasibility Grant application for a Brain Tumor Research Center from Northwestern University and its affiliated hospitals. Despite substantially increased knowledge about the biological behavior of malignant primary brain tumors and significant improvements in early diagnosis, survival of patients with brain tumors has not improved. This is the first application from a team of investigators that has been carefully assembled to bring clinical and basic research strengths to the study and treatment of brain tumors at Northwestern University. Additional faculty recruitments are now occurring and more are planned over the three year period of this feasibility grant, which, when completed, will bring the research and clinical complement of the team to a point it can conduct extensive collaborative basic and clinical research and can successfully compete for a full Program Project Grant application in three years. The central theme of this application is angiogenesis and its functional consequences. Angiogenesis is an obligate consequence of primary brain tumor growth, and yet the function of the new vessels may be nearly normal or wildly abnormal, particularly with regard to the one vessel property that most affects brain tumor therapy, i.e., permeability. The four projects in this application will focus on the two polar aspects of angiogenesis, the factors controlling initiation, and, at the other pole, vessel behavior and responses to therapy in fully developed tumors. These projects will attempt to bring these very basic and applied poles together. Project 1 will focus on the altered properties of brain tumor blood vessels by measuring blood- to-tissue transport in malignant gliomas, oligodendrogliomas, and medulloblastomas, and responses to common therapy. This is a topic about which almost no quantitative information exists in humans, and yet which must ultimately form the basis for understanding delivery of any diagnostic or therapeutic substance to brain tumors. Project 2 is designed to explore the mechanisms of angiogenesis inhibition, focusing on the role of copper dependent enzymes in growth factor-protease interactions. Project 3 intends to develop novel in vivo methods for measuring the development of angiogenesis and the effects of therapy. These new methods will add to our knowledge base about the vasculature of brain tumors, allow us to predict the behavior of brain tumor vessels, and serve as the basis for modeling drug delivery to brain tumors. Project 4 hypothesizes that proteolytic enzyme production in gliomas can be related to the aberrant expression of proto-oncogenes, and will study proto-oncogene products, secondary cellular messengers, and proteolytic enzymes, and determine if these can be related to angiogenesis and capillary function. No therapeutic studies are included in this application, but therapeutic trials of angiogenesis inhibitors are currently being designed and will become an integral part of this program within the first year.
