Recent advancements in genetic technologies reveal the possibility to ask new and previously inaccessible questions. The word metabolism, coming from the Greek Μεταβολισμός or “metabolismos” (translated means change) has already been known since the thirteenth century to indicate any transformation that the human body would encounter. Later on, the first organic molecules were discovered, but only with the 20th century and Hans Krebs and other notable biochemists, the field exploded and led to the assembly of what is known to us as the metabolic map. One of the drawbacks of these studies that could not be assessed with the available technologies at the time, resided in the lack of large part of the knowledge necessary to reveal the higher links that are present between cellular growth processes or signaling pathways and enzymatic reactions that were leading to the production of metabolites. Furthermore, still nowadays most of the Pubmed entries for metabolic enzymes are about the kinetic analysis of the reactions that they catalyze in their purified form, thus abstracted from their cellular environment. Synthetic lethality (SL) is a genetic phenomenon originally observed in Drosophila melanogaster by Bridges in 1922 and the term later coined by Dobzhansky in 1946, to describe complementary lethal systems in wild-type population of Drosophila pseudoobscura. It refers to cases in which the combination of two genes inactivation or mutations, which singularly are non-lethal, yields to lethality . This effect can be derived from the loss-of-function of two genes that act in parallel in redundant pathways, or belong to the same essential pathway or act in two distant pathways that are needed to react to a specific cellular perturbation. Questioning synthetic lethality is thus an elegant approach to study and link cellular growth processes dependent on genes and pathways in a systematic way. It promises to identify new therapeutic targets in different disease setting where either metabolism or growth defects are observed. Furthermore, cancer, which is due to an uncontrolled proliferation, has been shown to be surrounded by a different microenvironment, both immunological and at the nutrient levels. Regarding the presence of different nutrients, we already know that this is a quite distinctive feature of cancer, and indeed we use it in diagnostics when we measure glucose uptake in PET scans.
So far, synthetic lethality has offered its first approved drug (PARP inhibitors) for ovarian cancer mutated for BRCA genes. This therapeutic approach arrived to the clinic with an unprecedented speed. It is therefore the objective of this project to seek new genes within metabolic conditions, which are synthetic lethal to human cancer mutations. In this way new therapies could be designed against those targets and brought to the clinic faster than with single agents.
