Category: Chemical Biology

1054-E - Modulating endothelial cell metabolism for anti-angiogenic and cancer drug discovery

Wednesday, February 7, 2018
11:30 PM - 12:30 PM

Angiogenesis contributes to major pathologies such as blinding ocular diseases, inflammation and cancer. Insufficient efficacy, resistance and toxicity restrict the success of current therapies. There is an urgent need for novel strategies which should be based on fundamentally different mechanisms. We demonstrated recently that changes in the metabolic state of endothelial cells (ECs) are critical for vessel sprouting. We also showed that pharmacological inhibition of selected enzymes leads to inhibition of EC metabolism in vitro and normalization of vessel sprouting in vivo, providing proof-of-concept for targeting EC metabolism in angiogenic and cancer diseases.
We follow two strategies for the identification of most suitable drug targets and the development of novel therapeutics. In our targeted approach we are investigating well-characterized metabolic pathways in primary human ECs by inhibiting key enzymes via genetic and pharmacological means. We also developed an innovative strategy to broaden our search for drug targets in an unbiased and untargeted manner. As there are more than 4.000 metabolic enzymes reported so far, we constructed a bioinformatics platform composed of our in-house developed multi-omics data analysis software BIOMEX for target ranking. We then combined this technology with our genome scale metabolic modeling tool GEM to allow a functional prediction of target manipulation. Both tools complement each other for metabolic target discovery and already allowed us to identify multiple new targets in tumor ECs. We will report on the latest data from our targeted approach, using small molecule inhibitors of the validated cancer target PFKFB3 as an example. In addition, we will present details of our screening and validation strategy for novel targets.

Wolfgang Fecke

Expert, Discovery Biology
Leuven,, Vlaams-Brabant, Belgium

Wolfgang Fecke obtained his PhD in 1994 at the Heinrich-Heine University in Düsseldorf on the function and assembly of protein complexes of the mitochondrial electron transport chain. After a postdoctoral fellowship at Columbia University, he worked as group leader in several pharmaceutical and biotech companies in the UK (Imutran/Novartis, UCB Celltech), Germany (Callistogen) and Italy (Siena Biotech) on drug discovery programs, always with a focus on assay development, screening and lead profiling. In 2015 he joined the newly established VIB Discovery Sciences group in Leuven. He supports VIB researchers in developing biological assays and workflows for the efficient identification and characterization of new therapeutics for cancer, inflammatory and CNS diseases.