Targeting the oncogene ERG in prostate cancer with splice switching oligonucleotides

Dr Michael Ladomery from UWE Bristol's Centre for Research in Biosciences is currently developing splice switching oligonucleotides (SSOs) targeted against the ERG oncogene, and oncogene that is activated in a staggering proportion (~50%) of prostate cancers.

The research is funded by a Prostate Cancer UK Research Innovation Award. The research team currently comprises Dr Michael Ladomery (Principal Investigator), Dr Sean Porazinski (Research Fellow at UWE Bristol), Dr Sebastian Oltean (collaborator at the University of Bristol), and Dr Lee Spraggon (collaborator at the Sloan Kettering Memorial Cancer Center in New York USA).

Dr Ladomery's research group is focused on developing new strategies to treat cancer by targeting the 'pre-mRNA splicing machinery'. Pre-mRNA splicing is the process whereby exons are joined precisely together to form mature messenger RNAs. The latter convey the information from genes in order to produce proteins. 94% of human genes are 'alternatively spliced' so that genes can produce multiple mRNAs and therefore multiple proteins, often with opposing functions. Aberrations in the ratio of 'splice isoforms' contributes to the development and progression of cancer.

One potential therapeutic approach is to test small molecule inhibitors of 'splice factor kinases'. By inhibiting the splice factor kinase SRPK1, Dr Ladomery and colleagues have shown that its inhibition blocks angiogenesis and tumour growth in vivo. A second approach, the focus of the current project, is to target specific oncogenes with antisense oligonucleotides. The SSOs are a class of antisense oligonucleotides designed to block the splicing of specific exons, thereby correcting faulty splicing, or blocking the expression of oncogenes such as ERG.

Speaking about the importance of the research Dr Ladomery explains that “Prostate cancer is a huge health problem in the UK and worldwide. The 'ERG' gene and the protein it produces seem to be a key factor in the development and spread of at least 50% of cases of prostate cancer. We hope to develop a unique way to target this gene, and in the process learn more about the biology of this important oncogene”.

The research is one of a growing number of projects in relation to cancer research here at UWE Bristol. Dr Ladomery has built productive collaborations with colleagues at University of Bristol, as well as other experts around the world.

Please email Dr Michael Ladomery at Michael.ladomery@uwe.ac.uk for more details.