Ewa Szczurek

Predicting synthetic lethality in cancer



Cancer is a disease of the genome and one of the main causes of death worldwide. Recently, a strategy exploiting synthetic lethal (SL) interactions among genes was proposed as an invaluable aid for guiding new cancer therapy development. SL is a gene interaction where the co-inactivation of two genes results in cellular death, while inactivation of each individual gene is viable. The mechanism behind the success of SL-based therapy in cancer is that one inactivation already occurs via the endogenous mutation of a specific gene in the tumor cells, and not in the normal cells throughout the rest of the body. Thus, applying a drug that targets the SL partner of that gene will selectively kill cancer cells, leaving the rest viable (see Figure).

In this project, we plan to generate a list of SL partners of genes mutated in cancer. To this end, we wish to combine evidence in tumor profiling omics data (Figure A), evolutionary history of genes (Figure B) and off-target aware analysis of siRNA essentiality screens (Figure C) to come up with well supported predictions of SL (Figure D). We will next scan the predicted SL partners for targeting compounds, in this way collecting candidates for drug repositioning and candidates for drugs in general (Figure D,E). Finally, those candidate compounds will be experimentally verified, testing the identified SL interactions (Figure F).

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 665778. The funding was granted within the POLONEZ program from the National Science Centre in Poland, grant no. 2015/19/P/NZ2/03780.
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