Scientists achieve vital step on the path to drugging brachyury in chordoma

In recent years, researchers have identified chordoma’s Achilles’ heel: a protein called brachyury, which drives and sustains the cancer. To date, attacking brachyury has been an uphill battle. But new research has helped illuminate the path forward: with support from the Chordoma Foundation, scientists demonstrated that brachyury could be directly degraded and that doing so caused chordoma cells to stop growing.

“This study further boosts our confidence in pursuing brachyury as a drug target,” says lead author Dr. Hadley Sheppard of the Institute of Cancer Research, London (formerly of Baylor College of Medicine, where this work was conducted). Adds principal investigator Dr. Charles Lin, now at Kronos Bio, “More work is needed to see whether the findings will be replicable under conditions that more closely mimic human tumors, but the halt in chordoma cell growth was quite striking.”

Brachyury belongs to a class of proteins called transcription factors, which have been considered “undruggable” because they lack structural features to which traditional drugs can readily bind. But a game-changing technology has recently entered the scene: targeted protein degradation, which helps our cells remove undesirable proteins. The promise of this technology is being explored in a suite of Foundation-funded brachyury drug discovery projects.

To mimic what could happen with an eventual brachyury degrader drug, Dr. Sheppard’s team replaced the native brachyury protein in chordoma cells with an engineered version that could be instructed to degrade on command. They were pleased to find that when brachyury is degraded in these cells, they permanently and irreversibly stopped growing — even if brachyury levels increased again. They also became increasingly sensitive to cell death, which means they could be more susceptible to treatment with chemotherapy drugs that normally do not function well in chordoma.

Further, by mapping how brachyury is regulated in chordoma cells, the investigators found that brachyury drives its own production by physically assembling into a liquid droplet in the cell, resulting in a positive feedback loop that keeps it turned on at the high levels required for tumor growth. Using this feedback loop as a potential point of attack, the researchers found that degrading brachyury, even temporarily, broke the cycle that keeps brachyury switched on. They also observed that an existing class of drugs called transcriptional CDK inhibitors could disrupt the feedback loop and shut down brachyury, though not quite as quickly or specifically as direct brachyury degradation. Nevertheless, while brachyury-degrading drugs are being developed, transcriptional CDK inhibitors represent a highly promising interim approach and are already being explored through the Foundation’s Drug Screening Program.

In addition to these important findings, Dr. Sheppard and colleagues created a set of tools — engineered cell lines and laboratory tests — that will be indispensable to anyone seeking to develop drugs against brachyury. As the evidence grows for brachyury as a therapeutic target, so too will the demand for these tools. They will be made publicly available and easy to access, in keeping with the Foundation’s commitment to removing the traditional barriers that impede rapid scientific progress.

Taken together, this project adds to encouraging and increasingly urgent evidence that brachyury degradation is a strong therapeutic approach to chordoma. It dovetails into ongoing Foundation-supported research to develop compounds that directly block or degrade brachyury. And because brachyury seems to play a role in the metastasis and treatment resistance of more common cancers — including breast, lung, and colon cancer — the ability to attack it may hold implications far beyond chordoma.

With continued investment, drugs targeting brachyury could be brought into clinical trials within a few years.