This innovative research project is being led by Dr Hadley Sheppard in collaboration with Professor Paul Workman at the Institute for Cancer Research in London. The team will study chordoma dormant cells which could re-enter their reproductive cell cycle, increasing chances of reoccurrence. They will also be testing the effects of new drugs on these cells to see if they can be completely killed.

This innovative research project is being led by Dr Hadley Sheppard in collaboration with Professor Paul Workman at the Institute for Cancer Research in London. The team will study chordoma dormant cells which could re-enter their reproductive cell cycle, increasing chances of reoccurrence. They will also be testing the effects of new drugs on these cells to see if they can be completely killed.

Chordomas are unresponsive to conventional chemotherapy; the current standard of care for the disease is surgery followed by radiation. It is estimated that 40% of chordomas may recur and therefore, we need targeted drugs that can effectively treat this rare type of primary bone cancer.

One of the most promising targets for chordoma is the protein brachyury, which is encoded by the brachyury gene (TBXT).

The TBXT gene is only active for a brief period of time during human development, when it helps create an early form of the human skeleton. After this, the TBXT gene is switched off. If TBXT becomes reactivated in adulthood, it can contribute to the uncontrolled growth of cells and the development of chordoma.

Finding ways to switch off the TBXT gene or inactivating the brachyury protein is crucial to finding new drugs to treat chordoma.

Dr Sheppard has already discovered that switching off the TBTX gene or promoting the degradation of the brachyury protein in chordoma cells may not kill them completely; in some cases, it stops their growth and puts them into a dormant state that is known as “senescence”. Senescent cells may re-enter their reproductive cell cycle which could result in a tumour reoccurrence.

An emerging class of drugs known as “senolytics” have been shown to selectively kill senescent (dormant) cells in other cancers and could have potential for chordoma patients.

With this funding, Dr Sheppard aims to:

  • Study senescent (dormant) chordoma cells
  • Test senolytic drugs in combination with ways that switch off the TBTX gene or inactivate the brachyury protein to assess their effect on killing chordoma cells

How could this project improve treatment options for chordoma patients?

This research has the potential to enhance the effectiveness of targeted drugs for chordoma, making sure that dormant cells are destroyed, so that chordoma growth is fully and permanently halted, preventing tumour recurrences, and reducing metastases.