Ana BELOQUI GARCIA

Rewiring of energy metabolism is a key hallmark of cancer cells. In this regard, it recently became clear that certain cancers produce high levels of serine and glycine, and that these cancers get addicted to their own serine/glycine production to sustain their excessive growth. In the first part of this work, we showed that also acute lymphoblastic leukemia belongs to the rapidly expanding group of serine/glycine synthesis addicted cancers. The second part of this study aimed at identifying clinically applicable drugs that target serine/glycine synthesis, as this is a specific vulnerability in certain cancer cells but not in healthy cells. By screening serine/glycine synthesis addicted yeast and breast cancer cell models, we identified the clinically used anti-depressant sertraline (Serlain, Zoloft) as a specific inhibitor of serine/glycine synthesis. We showed that a drug combination including sertraline efficiently impairs proliferation of serine/glycine synthesis addicted breast cancer cells in a mouse model. Our work thus supports that sertraline has the potential to be an attractive adjuvant therapeutic agent to treat the rapidly growing list of serine/glycine synthesis addicted cancers.

The main limitation of current treatments relying on oral GLP-1 administration is their low and highly variable biovailability (1%). Studies in the field of metabolism exploring the physiological stimulation of GLP-1 secretion using different lipid ligands (e.g., butyrate, propionate) have failed to reach sufficiently high levels of GLP-1 in order for these to be considered as plausible treatments for metabolic disorders. We have developed a lipid-based drug delivery system (nanocapsules) that combines the physiological stimulation of endogenous gut hormone secretion (including GLP-1) with increased plasmatic levels of an encapsulated synthetic peptide. In addition, we have proven that this system does not only stimulate GLP-1, but also other gut hormones such as GLP-2, GIP or PYY. We were able to demonstrate the ability of these lipid-based nanocapsules to yield levels of the selected peptides that are therapeutically relevant in the context of different diseases, demonstrating the potential of this strategy to be used in the treatment of gastrointestinal/metabolic disorders (e.g., the so-called metabolic syndrome).

This research has been conducted at the Advanced Drug Delivery and Biomaterials (Louvain Drug Research Institute) at the UCLouvain. The research has also benefited from the expertise of the research group of Prof. Patrice D. Cani (UCLouvain), the research groups of Prof. Fiona Gribble and Frank Reimann (University of Cambridge, UK) via the ERC starting grant project Nanogut and Prof. Daniel J. Drucker (University of Toronto, Canada). The nanocapsules described in this proposal are the subject of a patent (patent Lipid nanocapsules charged with incretin mimetics (PCT/EP2020/064766 24.12.2020)).