Chordomas are unresponsive to conventional chemotherapy; the current standard of care for the disease is surgery followed by radiation. Is estimated that 40% of chordomas may recur and therefore, we need targeted therapies that can effectively treat this rare type of primary bone cancer.
One of the most promising therapeutic targets for chordoma is the protein brachyury, which is encoded by the brachyury gene TBTX.
The TBXT gene is only expressed for a brief period of time during human development, when it helps create an early form of the human skeleton. After its biological task is completed, the TBXT gene is switched off. Active TBXT in adulthood contributes to uncontrolled growth of cells and the development of chordoma. Switching off the TBXT gene or inhibiting the brachyury protein are therefore very attractive approaches to find new therapies for chordoma.
Dr Hadley Sheppard at the Institute of Cancer Research London has discovered that turning off the brachyury gene or degrading the brachyury protein in chordoma cells may not quite kill them completely, rather it stops their growth and puts them into a dormant state that is known as “senescence”.
We ideally want to kill brachyury downregulated/degraded chordoma cells as there is a concern that senescent cells may re-enter their cell cycle, and start dividing again, which could result in a tumour reoccurrence.
What are the aims of this research project?
An emerging class of drug molecules known as “senolytics” have been shown to selectively kill senescent (dormant) cells in other cancers.
Dr Sheppard aims to study in detail the extent and timing of the dormancy of chordoma cells caused by brachyury degradation or downregulation. She will also test senolytic drugs in combination with brachyury downregulation/degradation, to assess their effect on chordoma cell killing.
How could this project improve treatment options for chordoma patients?
This research has the potential to enhance the effectiveness of targeted therapeutics for chordoma, making sure that dormant cells are destroyed, so that chordoma growth is fully and permanently halted, preventing tumour recurrences, and reducing metastases.