Primary brain tumors
Ph.D. project:Background and purpose: New treatment strategies targeting the most frequent and malignant brain cancer – the glioblastoma – are urgently needed. Patients with this cancer have the highest number of years of life lost among all cancers. Tumor recurrence after standard treatment is inevitable due to migrating tumor cells that cannot be removed by surgery and don´t respond to chemoand radiation therapy. Brain cancer cells quickly migrate into the normal brain tissue, but only little is known about these cells, and how they can be targeted by new treatment. We have identified a new gene in these migrating cells, and this gene may represent a novel target gene. In contrast to previous research, the migrating cells we have studied, maintain their immature and aggressive characteristics, including the ability to generate new tumors. Initial investigations of gene-data suggest that the identified gene is associated with short survival, especially in recurrent tumors. The purpose of this project is to investigate whether the gene: 1.Increases migration of brain cancer cells 2.Is involved in the formation of tumors 3.Increases resistance to chemotherapy treatment 4.Is associated with short patient survival. Project placement regarding existing knowledge: The majority of research focuses on the properties of those cancer cells that easily can be removed by surgery, despite the fact that the non-removable migrating cancer cells have already migrated into the brain at time of surgery, thereby being the origin of tumor recurrence. These migrating cancer cells are resistant to chemo- and radiation therapy and not much is known about them, since they are difficult to investigate. We have investigated these migrating cancer cells with a new methodology, and identified a candidate gene, that could potentially be a new target for therapies targeting migrating cancer cells. Methods: We will use already established laboratory techniques and animal models based on well characterized brain cancer cells from patients. Using cancer cells where we have over-activated or shut down the candidate gene, we will investigate its role in migration, its influence on tumors formation, as well as its influence on efficiency of chemotherapy. In addition, we will use sets of already collected tissue samples from patients, to investigate the presence of the gene´s corresponding protein in the migrating cancer cells (30 patient samples). We will compare the amount of protein in primary and recurrent tumors (100 patient samples) and the protein´s role in patient survival (225 patients from Odense University Hospital + 174 patients from an international trial published in the highly recognized journal Lancet Oncology). Collaboration: We work together with Prof. G. Reifenberger from Germany, who is an expert in overactivation/shut down of genes in cancer cells. Investigation of the 174 patients from the clinical trial will be performed in collaboration with A. Malmström/P. Söderkvist in Sweden. Perspectives: Having identified a novel target in migrating tumor cells, we can turn this knowledge against brain cancer from a therapeutic point-of-view. The results will lay the foundation for the development of a novel type of targeted therapy preventing/reducing migration and tumor recurrence. The results could also be important in other types of cancer, since many cancers recur because the migrating cells cannot be removed by surgery or targeted with chemo- and radiation therapy. Treatment that eliminates migrating cancer cells is most likely a prerequisite for curative treatment of patients with many different types of cancer. In order to complete this project we must: -Overactivate/shut down the candidate gene in brain cancer cell lines established from patient biopsies. -Investigate the gene´s importance for the cells´ ability to migrate into brain tissue, form new tumors, and survive chemotherapy. -Investigate the presence of the gene´s corresponding protein in already collected tissue samples from patients. We will investigate migrating cancer cells (30 patients), primary vs. recurrent tumors (100 patients), and tumors from 399 patients with known treatment regimens, to see if the protein relates to patient survival and treatment regimens.