Genetic alterations are the hallmark of cancer. A European team is investigating a therapeutic strategy that restores the action of a natural anti-cancer gene.
Cancer remains one of the biggest challenges today, causing 1.7 million deaths annually in the EU alone. It is characterised by genetic heterogeneity which hampers the development of a common treatment approach. Nonetheless, 15-20 % of tumours present with mutations in the tumour suppressor protein p53. A key regulator of the cell cycle, p53 mutations destabilise the protein and inactivate its ability to mediate apoptosis under physiological conditions.
The idea behind the EU-funded 'Directed evolution of small-molecule cancer therapeutics' (DEVOCAT) project is to utilize simple microbes to develop drugs that can restore p53 protein activity and function as an anti-cancer therapy. The approach entails the synthesis of small molecules to restore the three-dimensional folding and function of the mutant p53.
Biosynthesis takes place within microbial cells, leading to a vast array of small-molecule compounds with high chemical and structural diversity. So far, approximately 10,000,000 such compounds have been synthesised and are being screened in a high-throughput genetic system. The output of this system evaluates the ability of each compound to improve the folding of the mutant p53 protein and its function.
The function of the p53 protein will be assessed through different biochemical and biophysical methods. The most promising candidate molecules will be tested in cancer cell lines for their apoptotic capacity.
Overall, the concept of the DEVOCAT study offers a promising alternative to standard approaches for cancer therapeutics discovery. It would be interesting to determine if this approach works in vivo, as cancers are known for their constant ability to evolve and evade cell death
Provided by Cordis