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GEnetic NEtworks as a tool for anti-CAncer Drug Development

Final Report Summary - GENECADD (GEnetic NEtworks as a tool for anti-CAncer Drug Development)

The objective of the GENECADD project was to develop a novel method for drug discovery by combining phenotypic cell-based screens with functional genetic networks to determine the molecular mechanisms of numerous small molecule inhibitors and identify novel targets for anti-cancer therapy.

Cancer cells harbour gene mutations or other specific phenotypes that make them more reliant on alternative cellular pathways for survival. These alternative cellular pathways can be targeted to selectively kill the cancer cells using the concept of synthetic lethality. Synthetic lethality describes the relationship between two proteins where loss of one has no significant effect on viability, but simultaneous loss of both leads to cell death. During the course of this project we have identified a novel concept for anti-cancer treatment based on synthetic lethality with the cancer phenotype i.e. cancer phenotypic lethality where we target a non-essential gene generally becoming essential in cancer. Based on this concept we have developed highly selective and potent inhibitors to proteins such as MTH1 with the aim to generate novel anti-cancer treatments.

We have performed large scale screening analyses to identify all synthetic or phenotypic lethal interactions between homologous repair (HR) proteins involved in repairing damaged DNA in cells with the aim to create a functional genetic network to understand the interplay between HR proteins. Parallel to this we have screened libraries of small molecules to identify inhibitors of HR. GENECADD has identified several inhibitors targeting DNA repair proteins which can either be used further as tools to increase our understanding of the molecular mechanisms of diseases such as cancer – or are currently being developed into potential novel treatments. Many of our inhibitors have been shared within the scientific community to increase our understanding of how we best can treat diseases such as cancer.

The overall aim of this research project was to develop more effective and selective treatments for cancer, as well as providing mechanistic information about how these new drugs work.