Study title

The overall objective of our laboratory is to determine the biological mechanisms underlying brain tumour development and identify novel therapeutic targets that will block or reduce tumour progression. Our research group has been able to isolate two different phenotypes from human glioblastomas by orthotopic xenotransplantation in immunodeficient rats (Sakariassen et al 2006). This model provides a tool for an isolation of a highly migratory non-angiogenic phenotype that display stem cell properties. Upon serial transplantation in animals, the tumors derived from the stem cell tumors will develop angiogenesis-dependency. The transition from angiogenesis-independent growth to angiogenesis- dependency is characterized by a down-regulation of pro-invasive genes and a loss of stem cell markers. Recent observations in our laboratory have shown that the cancer stem-cell phenotype use anaerobic metabolism (glycolysis) and that these metabolic events most likely are coupled to PI3K-Akt activation. Our hypothesis, based on current knowledge, is that the cancer stem cell phenotype eventually undergo a phenotypic shift to aerobic metabolism and that this shift is epigenetically regulated. In a search for novel therapeutic targets we will perform a detail analysisof epigenetic events downstream from the PI3K-Akt pathway, especially focusing on the glycolytic pathways. We will also perform detailed proteomic analysis (iTRAQ technology) of isolated membrane fractions obtained from the two phenotypes. We have sucessfully implemented this technology and several putative targets have been identified. These will be validated in clinical material. Moreover, we have developed new animal models that will allow us to further refine the isolation of the two phenotypes described. These eGFP expressing mice will allow a clean separation of the tumor host compartment of the phenotypes described.