Development of inhibitors of LDHB tetramerizatuion to block oxidative lactate metabolism and signaling in cancer

  • Sonveaux, Pierre (PI)
  • Frédérick, Raphaël (CoI)
  • Wouters, Johan (CoI)
  • Piel, Géraldine (CoI)

Project: Research

Description

Cancers have a high metabolic plasticity that allows cancer cells to adapt
and to evolve in hostile environments often characterized by oxygen and
nutrient deprivation. Among metabolic pathways, the oxidative pathway of
lactate singles out as it at the core of a metabolic symbiosis in cancer, it
stimulates cancer cell survival through autophagy and promotes
angiogenesis. While a first inhibitor of MCT1, the main transporter
controlling lactate uptake by oxidative tumor cells, is currently in clinical
trials for cancer patients, MCT1 ubiquitous expression, multiplicity of
substrates and documented resistance mechanisms temper enthusiasm.
Here, based on recent experimental evidence, we propose to rather target
lactate dehydrogenase B (LDHB) the enzyme that catalyzes the conversion
of lactate + NAD+ to pyruvate + NADH + H+ downstream of MCT1.
However, LDHB shares with other LDH isoforms a very similar catalytic site.
We will thus follow an original strategy that targets LDHB tetramerization,
hence activity, based on our recent identification of a 19mer dominantnegative
peptide (tetraLDHB) that possesses this activity. Our tasks in this
4-year research program will be 1) to elucidate precisely, using chemical
and biophysical methods, the hot spots responsible for tetraLDHB binding to
LDHB monomers in order to refine the structure of the peptide, 2) to
generate appropriate vectors for peptide delivery selectively in cancer cells,
and 3) to comparatively assess the physiological and tumoral
consequences of MCT1 and LDHB inhibition using as models in MCT1+/-,
LDHB+/- and LDHB-/- mice. Our multidisciplinary and interuniversity
consortium thus aims to validate therapeutic peptides targeting an
unprecedent anticancer target, which will also serve for the future
development of non-peptide LDHB inhibitors for anticancer therapy.
Short titleLDHB inhibitors
StatusActive
Effective start/end date1/10/1830/09/20