Project 460571

The presently incurable brain cancer, called glioblastoma (GBM), triggers formation of strange blood vessels, which play a role in disease progression as a source of nutrients, stimulants, and tracks of invasion. We have recently uncovered two unique aspects of blood vessel pathology in GBM that could be, but have not yet been, considered for new form of targeted therapy. First, tumour blood vessels differ depending on the molecular repertoire of cancer cells, in that the, so called, proneural GBM cells trigger formation of thin and dense blood vessel networks (likely driven by the well studied process known as angiogenesis). ln contrast, mesenchymal GBM cells induce networks of very large blood vessels of unknown nature. Second, we uncovered a process, during which small pieces of mesenchymal cells known as extracellular vesicles (EVs) or exosomes transmit the code (mRNA) for a cancer-specific (oncogenic) protein (called EGFRvlll) into blood vessel cells, change them, and trigger vessel enlargement. We call this latter process 'vasectasia'. Our preliminary data shows that when we block angiogenesis and vasectasia, mice with GBM live much longer, and we wish to explore this as an element of potential new treatment for mesenchymal GBM. To this effect we need to develop a better understanding of these relationships through the following series of studies: Aim 1. To understand what are the cancer vesicles (EVs) that trigger vasectasia. Aim 2. To dissect how these EVs change blood vessel cells, their molecular repertoire and function in mouse and human tumours. Aim 3. To assess how therapy directed at blood vessel responses can be integrated with standard treatment in brain tumours. We believe that this research will open a new window of opportunity for GBM patients who presently have no good options.