Dr Euan A Stronach

Team Leader: Molecular Therapy Lab

Euan gained a first class honours in Molecular Biology followed by a PhD in Medical Genetics from the University of Aberdeen. In 2000 he joined Prof Hani Gabra and his team at the, then Imperial Cancer Research Fund now Cancer Research UK, unit in Edinburgh as a postdoctoral fellow. From there he moved to Imperial College in 2003 where he now runs the Oncogenomics and Drug Resistance team within the Ovarian Cancer Action Research Centre. Euan is funded by Ovarian Cancer Action.

Molecular Therapy Lab:

Approximately 7000 women are diagnosed with ovarian cancer each year in the UK alone. Typically advanced stage at presentation and frequent development of resistance to chemotherapy are the major contributory factors to the poor 5 year survival rate for ovarian cancer.

The goal of the Molecular Therapy Lab is to discover new biology relating to the clinical phenotype of platinum resistance in ovarian cancer and utilise this knowledge for patient benefit. We have approached the problem primarily by identifying and investigating novel molecular mechanisms of resistance at the bench and are using this knowledge to attempt to improve the options available at the bedside for patients with platinum resistant disease.

Although the group’s activities are broad with numerous collaborative links, the core research we are carrying out stems from a gene expression profiling study, carried out by us, which identified changes in gene activity relating to chemoresistance in a series of isogenically paired cell lines modelling the transition from drug sensitivity to resistance as it occurred in individual ovarian cancer patients. Gene expression changes were initially identified by simple association and subsequently with supporting functional evidence using an in-house designed platinum resensitisation assay based around expression knockdown coupled to luminescent detection of apoptosis. By this approach we identified the genes PIK3R1, STAT1, FOLR2 and HDAC4 as being functionally involved in platinum resistance. The mechanisms by which these genes influence the cellular response to platinum is the focus of much of our activity and has led to the identification of a novel association between HDAC4 and STAT1 controlling STAT1 phosphorylation via an acetylation linked mechanism. In addition we have identified a novel activation mechanism of AKT following platinum resistance that involved the DNA repair protein DNA-PKcs. This work has branched out into collaborations with pharma around resensitisation to platinum treatment by co treatment with targeted small molecule inhibitors and collaborations in imaging science to detect the effect of targeting these mechanisms, non-invasively in vivo.

Immunofluorescent images of STAT1 activation following cisplatin treatment in platinum resistant (PEO4) ovarian cancer cells indicated by the phosphorylation and nuclear translocation of STAT1. Platinum sensitive cells (PEO1) taken from the same patient prior to relapse sho no such inducibility. Inhibition of STAT1 by siRNA causes resistant cells to become re-sensitised to cisplatin.