Laboratory of Angiogenesis and Vascular Metabolism
Peter Carmeliet’s laboratory focuses on one central topic ”Angiogenesis”, the growth of new blood vessels, in health and disease. Abnormal blood vessel growth, excessive or insufficient, contributes to multiple disorders, including cardiovascular disease, diabetes, cancer, age-related blindness, stroke, etc. Our ambition is to develop therapeutic concepts and, if possible, innovative anti-angiogenic treatments.
Latest findings indicate that the efficacy of current anti-angiogenic therapy (targeting VEGF) in cancer is limited by intrinsic refractoriness and acquired drug resistance. There is thus an urgent medical need to improve clinical anti-angiogenic therapy. To remedy this problem, Peter Carmeliet’s team uses a fundamentally distinct approach and pioneered the study of endothelial cell (EC) metabolism during angiogenesis, hypothesizing that targeting the metabolic “engine” of ECs would paralyze blood vessel growth and normalize tumor vessels. The role of several key metabolic targets in endothelial cell biology and tumor angiogenesis are currently studied.
The Carmeliet lab is also interested in unraveling the molecular basis of EC dysfunction and EC regeneration. EC dysfunction is of utmost importance in diseases such as diabetes, metabolic syndrome, etc., as it is a key determinant of cardiovascular morbidity and mortality, even when glycemia levels are under control. In fact, when becoming dysfunctional, the endothelium contributes to more (cardiovascular) diseases than any other cell type.
REVERSE EC METABOLIC PROFILING
Since little was known about EC metabolism, we started by selecting a particular metabolic target and studying the consequences of its over- or underexpression in ECs in vitro and in vivo on vessel sprouting (genotype-to-phenotype), termed “reverse metabolomics”:
PFKFB3: We showed that ECs are glycolysis-addicted (Cell 2013) and that partial, transient inhibition of glycolysis (by blockade of the glycolytic activator PFKFB3) sufficed to inhibit pathological angiogenesis without causing systemic effects (Cell Metab 2014). We also showed that low dose pharmacological PFKFB3 blockade induces tumor vessel normalization (TVN) and increases delivery and efficacy of chemotherapy (Cancer Cell 2016).
CPT1a: We reported that ECs (unlike cancer cells) use fatty acid (FA)-derived carbons in CPT1a-driven fatty acid oxidation (FAO) for de novo dNTP synthesis during EC proliferation, and that CPT1a blockade inhibits pathological angiogenesis (Nature 2015). We also showed that differentiation of venous to lymphatic ECs relies on the use of FA-derived acetyl-CoA as a signaling metabolite for epigenetic reprogramming of the differentiation switch (Nature 2016). Blockade of CPT1a inhibits pathological lymphatic growth, while replenishing acetyl-CoA levels by supplementing acetate rescues this process in vivo (Nature 2016).
FORWARD EC METABOLIC PROFILING:
In addition, we also perform the novel research line of “forward metabolomics” (phenotype-to-genotype) by isolating ECs from mice and patients with disease (cancer, diabetes, etc.), and by using state-of-the-art single cell RNA sequencing and advanced bioinformatics analysis, we are performing multi-omics profiling to identify metabolic targets that co-determine perturbed angiogenesis (such as in cancer or ocular disease) or EC dysfunction (causing cardiovascular disease in diabetics and neurological/neurodegenerative pathologies).
We aim to set-up a spin-off company, theranostics platform, focusing on two fields: ‘Therapy’ and ‘Diagnostics’:
Drug discovery platform: Key EC metabolic targets, identified in prior work by the Carmeliet lab, are subject to development of inhibitors against metabolic targets and early pharmacological validation. These targets will be the proprietary drug pipeline for further drug discovery by the company for tumor vessel normalization in cancer therapy. The Carmeliet lab, together with VIB drug discovery, aims to (i) screen several libraries for small molecule chemical compounds inhibiting metabolic targets and (ii) develop lead-to-hit compounds via medicinal chemistry in order to generate interest at pharmaceutical companies for further drug development and clinical translation.
Metabolic target and biomarker discovery: The bioinformatics software platform (BIOMEX), is further developed to improve discovery of co-blockade metabolic targets and metabolite biomarker identification (theranostics). We will utilize this platform to predict novel therapeutic metabolic targets in cancer to overcome therapy resistance, and to identify metabolic biomarker signatures that predict chemotherapy and immunotherapy response in different cancer patients
THE WORK OF PETER CARMELIET IS SUPPORTED BY: