CeMM: New method enabling therapeutical targeting of lactate transporters

Scientists from the Giulio Superti-Furga Lab at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, have developed a new method that allows the discovery of specific inhibitors of a lactate transporter associated with cancer and other disease areas. The compound identified in the assay system could provide a new starting point for cancer treatments. The study has now been published in Cell Chemical Biology.

Transporter proteins, including their largest class, the solute carrier (SLC) family, are proteins that are mostly located in the cell membrane and are responsible for the supply and removal of nutrients such as amino acids, sugars and nucleotides in a cell. They are key players in cell metabolism and play an essential role in health and disease. Despite their vital physiological role and although they are considered attractive therapeutic targets, most SLCs have not yet been adequately studied pharmacologically. This is precisely what numerous scientists in the research group of Giulio Superti-Furga, Scientific Director at the CeMM the Research Center for Molecular Medicine of the Austrian Academy of Sciences, and professor at the Medical University of Vienna, are working on. They have now developed a method to target lactate transporters SLC16A1 and SLC16A3, which are associated with certain cancers and other diseases.

Lactate, an end product of glycolysis, is known primarily as a metabolic waste product, but it is also used as an energy source. In fact, it has been shown that in many tissues, highly glycolytic cells secrete lactate, which is then used as an energy source by neighboring cells. This has been observed, for example, in skeletal muscle, brain, testes, and tumor microenvironment (TME). Lactate is transported across the membrane predominantly by members of the SLC16 family. Of four key lactate transporters, studies particularly attribute a central role to the SLC16A1 (MCT1) and SLC16A3 (MCT4) genes. Giulio Superti-Furga explains, “We know for more than a century that tumor cells tend to be highly glycolytic, and that the concentration of lactate can reach extreme levels inside tumors. But it is only relatively recently that we are starting to understand the consequences of this. For example, the high lactate levels are contributing to the suppression of immune cells inside the tumors, or to the development of resistance to treatment. Lactate transporters play a key role in this, especially SLC16A1 and SLC16A3, which are known as the major lactate importer and the major lactate exporter. Both transporters are considered promising drug targets.”

The study’s first author Vojtech Dvorak, PhD student in Superti-Furga’s lab, adds, “One of the major obstacles for the development of novel drugs that target SLCs are the frequent functional redundancies among several transporters that are present in cells. This makes it very difficult to isolate the impact of a potential drug candidate on a single transporter and hence determine the selectivity. In one of our previous projects, we found a synthetic lethality between SLC16A1 and SLC16A3 present in several cell models. This means that the cell normally has both transporters, and when one of them is either inhibited by the drug, or the gene for one of them is lost, the other transporter can compensate. However, if, for instance, the SLC16A1 gene is lost, the cell then becomes dependent on SLC16A3 for its survival (and vice versa). We realized that by creating several cell lines that are dependent on either of the distinct lactate transporters, we can use them to search for highly selective drugs.”

In the study published in Cell Chemical Biology, the scientists describe the development of the assay system called Paralog-dependent isogenic cell assay, or PARADISO for short, and its use to develop a highly selective chemical probe targeting SLC16A3, called slCeMM1. Superti-Furga concludes, “The lack of specific cell-based assays is a problem for many promising drug targets, not only for SLCs. The logic of the PARADISO assay system should be in principle widely applicable and helpful in finding new therapeutic targets.”

The study “Paralog-dependent isogenic cell assay cascade generates highly selective SLC16A3 inhibitors” was published on July 28, 2023, in Cell Chemical Biology (online ahead of print), DOI: 10.1016/j.chembiol.2023.06.029

Authors: Vojtech Dvorak, Andrea Casiraghi, Claire Colas, Anna Koren, Tatjana Tomek, Fabian Offensperger, Andrea Rukavina, Gary Tin, Elisa Hahn, Sarah Dobner, Fabian Frommelt, Andras Boeszoermenyi, Viktoriia Bernada, J. Thomas Hannich, Gerhard F. Ecker, Georg E. Winter, Stefan Kubicek, Giulio Superti-Furga

Funding: This work was supported by the Vienna Science and Technology Fund (WWTF LS17-051 Cellular Color Chart), the European Research Council (ERC AdG 695214 GameofGates) and the Austrian Academy of Sciences.

Giulio Superti-Furga is Scientific Director of CeMM, and Professor of Medical Systems Biology at the Medical University of Vienna. He was trained as a molecular biologist at the University of Zurich, Genentech, IMP Vienna, and EMBL Heidelberg. He obtained four grants from the European Research Council, is a member of five scientific academies, and has published more than 250 papers. CeMM, which he has been directing since 2005, is located in the middle of the large general hospital campus in Vienna, where, together with some 300 scientists and medical doctors, he brings genomic and systems views close to the clinical world with a view to improving medical practice. For CeMM, he promoted a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society and the arts. Recent interests include ways to create functional precision medicine approaches and the role of the human transportome in pathophysiology and drug discovery. He is the scientific coordinator of the Innovative Medicine Initiative consortium “RESOLUTE”, dedicated to the deorphanization of SLC transporters.

The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international, independent, and interdisciplinary research institution for molecular medicine under the scientific direction of Giulio Superti-Furga. CeMM is oriented toward medical needs and integrates basic research and clinical expertise to develop innovative diagnostic and therapeutic approaches for precision medicine. Research focuses on cancer, inflammation, metabolic and immune disorders, and rare diseases. The Institute's research building is located on the campus of the Medical University and the Vienna General Hospital. www.cemm.at

Medical University of Vienna (MedUni Vienna) is one of the most traditional medical education and research facilities in Europe. With almost 8,000 students, it is currently the largest medical training centre in the German-speaking countries. With 6,000 employees, 30 departments and two clinical institutes, 13 medical theory centres and numerous highly specialised laboratories, it is one of Europe's leading research establishments in the biomedical sector. MedUni Vienna also has a medical history museum, the Josephinum.  www.meduniwien.ac.at

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