Some of the most striking differences between cancer cells and normal cells are those found in metabolic pathways, which are the biochemical processes used by living organisms to support life.
Around the time of Agios’ founding in 2008, the field of cancer metabolism made important leaps forward, discovering that mutations in oncogenes and tumor suppressors exert their effects in part by accelerating and remodeling metabolic pathways. These breakthroughs suggested the potential to apply precision medicine approaches to cancer metabolism – a concept which remains at the core of our research strategy.
Scientists in the field thought that this remodeling by oncogenes and tumor suppressors occurred as a way to provide the building blocks required for rapid growth. Our work has taught us that there is more to the story: often, remodeling of metabolism in cancer happens not simply as a way to create building blocks, but rather to create metabolites that control the signaling and epigenetic pathways that drive tumors. One example of this is Agios’ discovery that mutations in IDH lead to production of an oncometabolite, 2-hydroxyglutarate (2HG), which exerts its pro-tumor effects by regulating epigenetic enzymes.
In our efforts to identify important anti-cancer targets, we have learned that the metabolome – the interconnected network of metabolic pathways – is very flexible, with many built-in redundancies. This flexibility creates challenges for drug discovery, as cancers can often bypass the effects of a small molecule drug by shifting to an alternate pathway. Guided by our precision medicine strategy, we have identified a number of cancer subsets where some of this metabolic flexibility is lost. These losses of flexibility often create a druggable vulnerability.
These vulnerabilities form the basis of several programs in our pipeline, and can arise due to:
Deletions in metabolic genes. A number of metabolic genes are deleted in some cancers sometimes called synthetic lethality and in some cases the loss of the deleted gene creates vulnerability to targeting of a second gene .
Restricted expression of metabolic genes in cancers from specific lineages. Individual cancers use only a subset of the genes in the metabolome, which can prevent the ability to bypass the effects of drug.
Differences in nutrient utilization. Some cancers become highly dependent on specific nutrients, creating dependence on the metabolic enzymes critical to metabolize the nutrient.