A small molecule inhibitor of histone deacetylases (HDACi) is currently in use for the treatment of refractory cutaneous T-cell lymphoma and more than eight HDACis are in clinical trials for use against a range of solid and haematological malignancies, either singly or in combination therapies. However, this approach is limited as cancerous cells develop resistance to HDACi treatment, through unknown mechanisms. No biomarkers are available to distinguish HDACi sensitive and resistant tumour cells. The route to generating resistant tumour cells to identify biomarkers and mechanisms is to induce tumours in mice and induce resistance in order to isolate cells. This uses many mice and involves protocols rated as moderate severity.
We will develop a non-animal model for HDACi resistance by exploiting the easy genetic manipulation of Dictyostelium discoideum to identify mutations conferring HDACi-resistance. Dictyostelium is an ideal model for studying histone modifications, as modifications are conserved between Dictyostelium and human cells, including a number not found in yeast. HDACis inhibit Dictyostelium development facilitating genetic screens for resistant mutants. A pilot screen successfully identified a candidate gene and we will extend this analysis.
We have two aims. 1. Characterising the histone modifications in resistant strains will identify bio-marker profiles associated with resistance. 2. Elucidating the mechanism of action of the proteins/RNAs encoded by target genes will increase our understanding of the mechanisms by which HDACis target tumour cells. This will facilitate targeting HDACis to responsive cancers and developing strategies (combination therapies or inhibitors with altered specificity) to overcome resistance, minimising use of animals.
Pears CJ and Lakin ND (2014). Emerging models for DNA repair: Dictyostelium discoideum as a model for nonhomologous end-joining. DNA repair 17:121-31. doi: 10.1016/j.dnarep.2014.01.008
Couto AM et al. (2013). Investigation of DNA repair pathway activity. Methods in Molecular Biology 983:295-310. doi: 10.1007/978-1-62703-302-2_16
Principal investigatorProfessor Catherine Pears
InstitutionUniversity of Oxford
Co-InvestigatorProfessor Louis Mahadevan
Professor Robin Williams