Targeting the Tumour Specific Energy Metabolism in Glioblastoma

Comprehensive phase III clinical studies have recently shown (2013) that anti-angiogenic therapy (bevacizumab treatment) for human glioblastoma leads to tumor resistance to therapy and no overall survival benefit was observed. We have in the present project identified key mechanisms responsible for glioblastoma resistance to anti-angiogenic therapy. Specifically, we have identified metabolic switch mechanisms in tumours as a response to anti-angiogenic treatment (bevacizumab therapy). We have shown by 13C6-glucose metabolic flux analyses in vivo, that such switch mechanisms involve an up-regulation of anaerobic respiration with a concomitant down regulation of oxidative respiration in the treated tumors. Based on a comprehensive molecular screening, we have identified new potential targets for therapy. These targets including the glycolytic enzymes HK2, PDK1 and PGAM1 are now in the process of being validated in our human orthotopic glioblastoma xenograft models in combination with anti-angiogenic therapy. The most important findings in the project are: 1) We have shown that the anti-fungal compound Posaconazole inhibits HK2 activity. In preclinical studies, we have shown that combinatorial treatment, Posaconazole(Bevacizumab potentiates the effect of anti-angiogenic therapy. 2) We have shown that Cannabidiol treatment inhibits hypoxia after anti-angiogenic therapy and that combined treatment with bevacizumab gives an increased therapeutic effect in human glioma xenograftmodels. Our research group will now work on getting this combined treatment principle into the clinic for patients with malignant brain tumours.

Glioblastoma multiforme (GBM) is the most aggressive brain tumour with a very poor prognosis. GBMs are highly angiogenic and show an infiltrative growth pattern in the normal brain. Recent studies show that antivascular therapy using the angiogenesis in hibitor bevacizumab (Avastin) reduces contrast enhancement and normalizes the blood vessels. Even though there is a short improvement of progression free survival, recent data indicate that there is no improvement in overall survival. This is based on th e fact that bevacizumab treatment seems to stimulate infiltrative tumor growth. We have now shown that the infiltrative tumour cells (which represents the main problem for tumor cure) use aneorobic metabolism (glycolysis) for their survival and that Beva cizumab treatment leads to a metabolic switch towards glycolysis. As a metabolic disorder involving dysregulation of glycolysis and respiration (the Warburg effect), we hypothesize that GBMs can be managed through induction of changes in the metabolic en vironment in combination with anti-vascular therapy. In this project we will:1) Identify metabolic switch mechanisms in tumours as a response to anti-angiogenic treatment and identify key molecules required for tumour adaptation to hypoxic conditions, 2) Determine if these switch mechanisms can be targeted in clinically relevant orthotopic animal models using a combination strategy with angiogenesis inhibitors and drugs that interfere with the glycolytic energy metabolism. 3) Select through collaboration, highly specific therapeutic molecules against the newly identified drug targets and validate them in preclinical GBM models.4) Design a new treatment protocol for GBMs by implementing the best combinatorial treatment principle in a proof-of-concept clin ical trial This application represents a paradigm shift in GBM treatment that is strongly based on detailed biological knowledge on how tumours develop metabolic escape mechanisms towards antiangiogenic therapy.