The main goal of this research is to use chemical compounds and epigenetic drugs to identify and validate novel tractable targets for the potential treatment of patients with chordoma.

Project summary

To understand the causes and development of bone cancer, Dr. Adam Cribbs (Oxford) and Dr. Lucia Cottone (UCL) have focused their research on identifying epigenetic pathways that contribute to chordoma biology.

Chordoma is a rare slow growing bone cancer that can occur in any of the bones from the base of the skull to the coccyx. Given its close proximity to the spinal cord, chordoma is difficult to treat, and very few drugs are available for inoperable and metastatic disease. To accelerate the discovery of new drugs available for patients, Dr. Cribbs and the team will test the efficacy of a panel of novel chemical compounds that inhibit the “epigenetic” cellular machinery to kill chordoma cells in vitro.

Epigenetics is the addition of information on top of the DNA sequence of letters (strings of molecules called nucleotides - A, G, C, T). This is achieved by adding a variety of chemical modifications, called marks, to the nucleotides and different epigenetic marks control the expression of different genes. Dr. Cribbs and the team have recently shown that a subset of such epigenetic marks controls the expression of brachyury, a gene critically involved in the development of chordoma, and that blocking these epigenetic mechanisms effectively leads to chordoma cell death in laboratory studies.

The development of new medicines is required to improve patient outcomes and quality of life. Therefore, in addition to drug screening, Dr. Cribbs and the team propose to complement this study with the creation and validation of an ‘epigenetic map’. Using this map, they will generate computer software as part of this project to identify regions of DNA that may be involved in the suppression of genes that drive chordoma development.

Overall, the goal of this project is to generate a shortlist of druggable epigenetic targets that can be used to advance drug development for chordoma. Moreover the ‘epigenetic map’ profiling will inform our understanding of the epigenetic mechanisms that govern chordoma development, thus allowing the identification of further potential therapeutic targets for this bone tumour.

How will it improve the lives of patients?

Short-term impact: The main outcome of this work will be to maximise the understanding of the contribution that epigenetic mechanisms play in chordoma transformed cells. Therefore, a primary outcome of our work will be to provide patients of chordoma with knowledge of potentially tractable targets for chordoma therapy.

Long-term impact: The research will be focused on generating a list of druggable targets to aid drug development pipelines. As such, the team envisage that a long-term patient benefit will be realised through the progression of one or more of these targets towards the clinic.