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