Targeting Cancer's metabolic vulnerabilities
Much have changed over the past decade in the way we perceive metabolism in cancer research and cancer clinical management. Several routes have led to this conceptual transformation, including technological achievements, genetic observations, diagnostic tools and pharmacological approaches. These have already instigated the development of novel therapies for cancer patients.
Cancer's metabolic vulnerabilities can be originated from the intrinsic metabolic demands associated with uncontrolled proliferation or from the metabolically hostile microenvironment to which tumors need to adapt. Furthermore, genetic alterations in metabolic genes that are linked to cancer initiation and progression can also provoke metabolic liabilities. Of these, the loss of succinate dehydrogenase (SDH) or fumarate hydratase (FH) in some tumors can indeed render cancer cells heavily reliant on metabolic adaptations for survival. SDH and FH are tricarboxylic acid (TCA) cycle enzymes while SDH is also part of the respiratory chain. Despite their key housekeeping activities, the genetic loss of FH or of any of the SDH subunits is associated with tumorigenicity. SDH or FH inactivation leads to the accumulation of succinate and fumarate, respectively. Consequently, these metabolites mediate a signaling cascade which causes the activation of hypoxia-inducible factors and the inhibition of histone and DNA demethylases, establishing pseudohypoxic and hypermethylation phenotypes. However, not much is known about the metabolic mechanisms which enable the survival and proliferation of these TCA cycle-defective cells. Overcoming the loss of SDH and FH requires a significant metabolic rewiring as backup mechanisms for the dysfunctional TCA cycle and oxidative phosphorylation. Identifying such adaptations would reveal effective and specific vulnerabilities of these metabolically atypical neoplasms which can serve as potential molecular targets for therapeutic intervention.
The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling