BBB seminar: Rolf Bjerkvig
Malignant brain tumours: Their initiation and progression and resistance mechanisms to anti-angiogenic therapy
Department of Biomedicine and K.G. Jebsen Brain Tumour Research Centre, University of Bergen
Our group focuses on malignant brain tumours (glioblastomas), which are known to have a poor prognosis, despite aggressive treatment consisting of surgery, radiotherapy and chemotherapy. In this seminar, the biological characteristics of glioblastomas will be described with special emphasis on our research programme aimed at understanding how they develop and progress. Moreover, an example will be shown related to anti-angiogenic therapy, and how tumours develop resistance to treatment. In a series of preclinical studies using intracranial patient-derived glioblastoma xenografts, we have shown that the tumours develop resistance towards anti-VEGF treatment by undergoing a metabolic switch towards glycolysis, as indicated by an up-regulation of the transcription factor hypoxia inducible factor-1 (HIF-1) and several metabolites associated with the glycolytic pathway (e.g. lactate). We have also delineated in detail the metabolomic changes that occur in the tumours after anti-angiogenic therapy (bevacizumab treatment). By performing 13C6-glucose metabolomic flux analyses, we have shown that the tumours undergo metabolomic re-programming towards anaerobic metabolism thereby uncoupling glycolysis from oxidative phosphorylation. Following treatment, an increased influx of 13C6-glucose was observed into the tumours, concomitant to increased lactate levels and a reduction of metabolites associated with the tricarboxylic acid cycle (TCA cycle). This was confirmed by increased expression of glycolytic enzymes. We have also performed a comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma, and identified novel drugs that may improve the effect of anti-angiogenic therapy. These are now being further validated in preclinical models.
Chairperson: Jaakko Saraste, Department of Biomedicine