For some time now researchers have been trying to neutralise a key player in the survival and multiplication of tumour cells, without much success. But today a team of researchers led by UCLouvain has found a completely new approach.
Every cell needs to ‘breathe’. That is, absorb gases and/or nutrients necessary for its survival. From this perspective, the cancer cells of a solid tumour[1] can be classified into two main categories:
- Oxidative cells are on the tumour’s periphery and surface. They breathe thanks to oxygen transported by small blood vessels which irrigate the tumour.
- Glycolytic cells are inside the tumour. Since their access to blood – and therefore oxygen – is limited, they have to breathe differently. To do this, they use and transform glucose (sugar).
Metabolic symbiosis
Lactate dehydrogenase (LDH) is an enzyme a priori expressed by all tumour cells. It plays a fundamental role in their metabolism. Indeed, LDH helps transform glucose into substances which allow cells – even those located at the tumour’s centre – to breathe. ‘From a biochemical point of view, it’s a fairly remarkable metabolic symbiosis system,’ explains Prof. Raphaël Frédérick, head of the UCLouvain Medicinal Chemistry Laboratory (CMFA). ‘Oxidative (peripheral) cells and glycolytic (internal) cells exchange lactate, a derivative of glucose transformed by LDH. This allows them all to live, function and, when necessary, reproduce.’
Hard to target
Given the fundamental role played by this enzyme, many researchers want to inhibit LDH. The goal is to prevent it from operating, thus depriving tumour cells of respiration. But LDH has proven to be a difficult target. ‘Certain molecules can inhibit LDH,’ Prof. Frédérick says. ‘The problem is that these molecules aren’t specific for LDH. They inhibit other enzymes, especially in healthy cells. Therefore, these inhibitors would cause side effects in the patient.’
A group of Belgian researchers has therefore opted for another, largely unexplored approach: targeting the tetramerisation site of LDH, that is, the enzyme’s construction site.
Changing the site and breaking the tetramer
Some enzymes do their job with just one unit; they form monomers. LDH is a tetramer: it needs to form a set of four units to be active. ‘So we were interested in the tetramerisation site. That is, where, when, and how the LDH assembles. The idea is to “break” the tetramer, or even prevent it from forming. In both cases, the inactive LDH would be unable to play its metabolic role. This would deprive tumour cells of their breathing.’
New multidisciplinary research tools
But before imagining a molecule capable of such sabotage, the researchers had to understand how the LDH tetramer is formed. To do this, they used a nuclear magnetic resonance (NMR) apparatus and micro-scale thermophoresis, a highly sophisticated optical technology. ‘These tools make it possible to study and analyse interactions at the molecular level,’ Prof. Frédérick explains. ‘For us chemists, these were new tools. But that's the beauty of this study, which is both multicentric [see box] and multidisciplinary. Léopold Thabault, the young researcher and first author of the recently published article on this research, has thus worked with fellow chemists, pharmaco-oncologists, and biophysicists.’[2]
A promising molecule?
After highlighting the LDH tetramer’s formation, the researchers found a first molecule[3] with promising effects. Their results are published in the Journal of Medicinal Chemistry. ‘In vitro, it greatly interferes with tumour cells’ breathing,’ Prof. Frédérick explains. ‘But it’s still too early to say that our molecule has a significant effect on their survival and, a fortiori, proliferation. We need to study it further, understand exactly its mechanisms of action, and check to what extent we could improve it and optimise its effects.’ And then, perhaps, create a new therapeutic path for fighting cancer.
One project, several funders
The ‘LDH disruptor’ project is a multicentric research project funded mainly by Télévie. It brings together two teams from UCLouvain (those of Profs Raphaël Frédérick and Pierre Sonveaux) and researchers from the University of Namur, the University of Liège, and VUB. Additional funding comes from the FNRS (which funded the micro-scale thermophoresis technology), the Cancer Foundation (which funded the NMR device), an ERC Starting Grant, and a Wallonia-Brussels Federation ARC grant.
Candice Leblanc
Video profile of Raphael Frédérick :
A glance at Raphael Frédérick's bio
Raphaël Frédérick is professor of medicinal chemistry at UCLouvain. He is vice-president of the Louvain Drug Research Institute (LDRI) and head of the Medicinal Chemistry Research Group. He is also an FNRS honorary associate researcher. He holds a master's degree in chemistry and a PhD in pharmaceutical sciences, obtained at the University of Namur, in 2006. A researcher at the University of Namur between 2007 and 2013, he joined UCLouvain in 2013 to teach and continue research in medicinal chemistry.
A glance at Léopold Thabault's bio
Funded by an FNRS grant, Léopold Thabault is pursuing his PhD at the LDRI Medicinal Chemistry Research Group. He earned a master’s degree in pharmaceutical sciences from UCLouvain in 2016. The same year, he received the Nedeljkovic Prize for outstanding academic achievement.
[1] A distinction is generally made between solid tumours, which appear and develop in a tissue (organ, fat, bone, etc.), and so-called liquid cancers, which affect blood cells (leukaemia or lymphoma).
[2] L. Thabault et al., ‘Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides’, in Journal of Medicinal Chemistry, 6 April 2020.
[3] (3) A peptide, a molecule made up of a limited number of amino acids.