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Targeting endothelial metabolism: a novel anti-angiogenic therapy

Final Report Summary - ECMETABOLISM (Targeting endothelial metabolism: a novel anti-angiogenic therapy)

The efficacy of current anti-angiogenic therapy (targeting VEGF) is limited by intrinsic refractoriness and acquired drug resistance, in part because VEGF-blockade upregulates the expression of additional pro-angiogenic factors. Even blocking these other angiogenic signals (together with blocking VEGF) is likely to incite additional escape mechanisms. There is thus a large unmet medical need to improve clinical anti-angiogenic therapy. In this ERC Advanced grant project, we used a fundamentally distinct approach and pioneered to study endothelial cell metabolism during vessel sprouting, hypothesizing that targeting this “engine” of endothelial cells would paralyze blood vessel growth, regardless of the available pro-angiogenic signals. We showed that glucose and fatty acid metabolism determine vessel sprouting (even overruling its genetic control), and that targeting these metabolic pathways inhibits pathological angiogenesis in various disorders.

Major breakthrough discoveries in this ERC ECMetabolism project include the following: (i) We showed that endothelial cells are glycolysis-addicted and that lowering of glycolysis only partially and transiently (by blockade of the glycolytic activator PFKFB3) sufficed to inhibit pathological angiogenesis without causing systemic effects. This paradigm-shifting discovery challenged the previous dogmatic approach to block glycolysis as completely and permanently as possible, but thereby also causing systemic toxicity (Cell 2013, Cell Metab 2013, Cell Metab 2014, Cell Cycle 2014, Nature Communications 2016), (ii) A screening cascade for PFKFB3 drug development is started (ongoing ERC proof-of-concept grant); those PFKFB3 blockers will be evaluated in pathological angiogenesis; and (iii) we discovered that endothelial cells use fatty acid-derived carbons for de novo deoxyribonucleotide synthesis for DNA replication, unlike cancer cells that use glucose and glutamine as main carbon source for this purpose. We translated this basic finding by showing that pharmacological blockade of the usage of fatty acids inhibits pathological angiogenesis (Nature, 2015).