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 therapies that can treat this rare type of primary bone cancer effectively, at doses that are well tolerated by patients.
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 active only for a brief period of time during development of the human embryo, when it helps to create an early form of the spinal cord. After this biological task is completed, the TBXT gene is switched off. However, in rare instances TBXT is turned back on again in adulthood – which contributes to uncontrolled growth of bone-like cancers in and around the spine, known as chordoma tumours. Switching off the TBXT gene or inhibiting the brachyury protein it encodes are therefore very attractive approaches to find new therapies for chordoma.
Based at the Institute of Cancer Research (ICR) in London, Professor Workman is an expert in the discovery of targeted anticancer drugs, having played an instrumental role in discovering two approved oncology drugs, and overall in the discovery of 20 drug candidates. He was motivated to apply his expertise to develop drugs for chordoma by the challenge of the fascinating and demanding science of brachyury, but also by loss of his mother, aged 68, as a result of a sacral chordoma. Read more here.
Professor Workman first became involved in chordoma research as a collaborator on a key study published by an international group of researchers that demonstrated convincingly by advanced techniques (known as genome-scale CRISPR-Cas9 screening) that brachyury was far and away the clearest 'cancer-driving' protein and represented a therapeutic vulnerability in human chordoma cell lines. The study also showed that small-molecule drugs that block the production of brachyury can give a therapeutic benefit, an approach that Professor Workman is still pursuing.
However, it became clear from this and a follow-up study that it would be better to develop new drugs that would work by binding directly to the brachyury protein target itself. The challenge, however, was that brachyury functions as a transcription factor – a protein that controls the activity of other genes; and like most transcription factor targets, the brachyury protein molecule is very tough to drug – lacking the sort of pockets that drugs are usually designed to fit into in order to exert their therapeutic effects.
Determined to tackle this problem, Professor Workman and colleagues established a follow-on international collaboration with researchers from the Structural Genomics Consortium (SGC) at Oxford University (Joseph Newman and Opher Gileadi) and the University of North Carolina at Chapel Hill, USA (David Drewry). Enabled by the use of the powerful X-ray beam and XChem facility available at the Diamond Light Source at Didcot, UK, the team recently published, in February 2025, their initial breakthrough research towards ‘drugging brachyury’ – work that was funded by the SGC, Chordoma Foundation and Mark Foundation.
What are the aims of this research project?
This key publication described the first 3D X-ray crystal structures of human brachyury, including the variant form strongly associated with chordoma, which shed light on how it functions as a transcription factor. They then used this detailed high-quality 3D structure to carry out an approach known as fragment-based screening, whereby very small chemical compounds (‘fragments’) were used successfully to identify hotspots they could bind to on the surface of the brachyury proteins.
Again guided by the 3D structure, the team improved the strength of binding of their initial series of chemical fragments, known as ‘ligands’. This importantly established for the first time that brachyury is ‘ligandable’ and therefore potentially ‘druggable’.
At this point the team published their findings so that other researchers, as well as themselves, could also use all the information to expedite progress towards prototype bracyhury-binding drugs for chordoma. To aid this, the collaboration has so far operated as an ‘open science’ project, whereby all the results are placed in the public domain with no patents filed at this early stage – so as to maximise the uptake and use of the vital information gained.
How could this project improve treatment options for chordoma patients?
This research has the potential to produce enhanced brachyury-binding ligands to use as informative, pathfinder research tools in cell culture and mouse models of chordoma – and then progressing to drugs that could be evaluated in clinical trials of chordoma patients. The overall aim is to discover brachyury-targeting drugs that would prevent tumour recurrences after surgery and radiotherapy, and also reduce metastases, thereby greatly improving the outcomes for chordoma patients.
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