Investigating toxic metabolite pathways and metabolite detoxifying enzymes in cancer

The notion of poisoning cancer cells with their own metabolites is an unexplored concept. We have created a framework to allow systematic investigation of this area, by compiling a list of endogenously produced metabolites in human cells which have toxic properties when allowed to accumulate, and the downstream genes which can metabolize the toxic metabolites, which we refer to as putative ‘metabolite detoxifying enzymes’ (MDEs). These enzymes represent novel, druggable candidates for exerting toxicity in cancer cells. We are investigating whether we can induce metabolic poisoning in a predictable, cancer subtype-specific manner by targeting these MDEs. Furthermore, we want to understand the physiological roles for these pathways and the underlying biological basis for the toxicity of these metabolites. We are exploring these questions using metabolite profiling, CRISPR-Cas9 genome editing, and small-scale pooled screening approaches.