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New paper confirms that brachyury is the Achilles' heel of chordoma, and reveals a new way to attack it

This is an exciting milestone in the quest for better treatments, and a big win for all involved in the research.


We're excited to share the findings of a new paper published earlier this week in the journal Nature Medicine that opens the door to a new treatment approach for chordoma. These findings result from a project the Foundation has been supporting involving a team of researchers led by Drs. Stuart Schreiber and Tanaz Sharifnia at the Broad Institute of MIT and Harvard.

It provides the strongest evidence yet that brachyury is the Achilles’ heel of chordoma, and, encouragingly, points to a new way to shut it off in chordoma cells using drugs that are already in clinical trials. Because this represents a significant milestone in our community’s quest for a cure, and has implications for those who may have exhausted other treatment options, I wanted to take a moment to provide some additional context and perspective.

Background on this project

As you’ve probably heard before, a protein called brachyury is the defining diagnostic marker of chordoma. In other words, the presence of brachyury is how pathologists can be sure that a tumor is chordoma. That was discovered in 2006 by Dr. Adrienne Flanagan and colleagues in London.

In the time since, a growing body of research in many labs has built a strong case that brachyury is not only always present in chordoma, but serves as a key driver of the disease, critical to its identity and essential for its survival. That coupled with the fact that brachyury is not present in normal tissue points to the exciting possibility that a treatment capable of shutting off brachyury could cure chordoma with minimal side effects – not just slow the disease, but actually cure it.

The challenge is that brachyury is a very difficult protein to develop drugs against using conventional drug discovery approaches. Specifically, it belongs to a class of proteins called transcription factors, whose structure lacks the kinds of “nooks and crannies” to which most drugs bind.

So, before investing in the development of new drugs against brachyury, our scientific advisors urged us to explore whether there might in fact be other equally promising targets in chordoma against which drugs may already exist – or which could at least be easier to develop new drugs against.

That led us to recruit and fund a team led by the Broad Institute to employ several advanced technologies to systematically search for new therapeutic targets in chordoma (see project announcement here).

All roads point to brachyury

The team set out to identify new targets with three different approaches in parallel.

The first was to ask what genes chordoma relies on for survival. We already knew that brachyury was one of them, but might there be others? To answer this question, they turned off nearly every gene in the genome one at a time in chordoma cells using CRISPR gene editing technology and observed which genes the cells couldn’t survive without.

Amazingly, of >18,000 genes tested, the gene that encodes the brachyury protein turned out to be the most critical in chordoma relative to a large number of other cell types. In other words, they found that brachyury is not just a vulnerability in chordoma, but the greatest vulnerability – it’s Achilles’ heel.

In parallel, as a second approach to identify new targets, they collaborated with Dr. Charles Lin (formerly at Dana Farber Cancer Institute, now at Baylor College of Medicine) to determine which genes chordoma cells commit the most internal resources to keep “turned on.” Knowing this may point to the genes most critical for driving the cancer. Again, amazingly, the brachyury gene rose to the top of the list.

Between those two findings, coupled with all the prior evidence about brachyury’s role in chordoma, it appears that in fact brachyury is the most central player. Based on that realization, we have made developing drugs that can target brachyury the Foundation’s top research priority. And, as you may have seen, last year we invested in several projects applying innovative technologies that promise to get around the challenges brachyury poses for conventional drug discovery (see more here).

But, meanwhile, the story wasn’t finished at the Broad.

A new way to attack brachyury

Taking a step back for a moment, the internal resources mentioned above refer to the cellular machinery involved in turning genes on (a process called transcription). Every cell in the body uses this same machinery – it’s an essential part of how cells work. Cells tend to allocate more of the transcriptional machinery to genes that are more important or more actively used.

When cells become cancerous, this allocation process sometimes becomes hijacked, resulting in a huge overabundance of transcriptional machinery getting devoted to genes that are key to driving the cancer (somewhat akin to an addiction, which drives an individual to spend huge amounts of money to continue to feed the addiction).

The team’s findings suggest that this addiction is exactly what’s happening with brachyury in chordoma.

Interestingly, researchers had recently discovered that in other cancers this pattern of addiction creates a weakness that can be exploited. Specifically, it turns out that the production of the genes to which the cancer is addicted – and has diverted excess transcriptional machinery — becomes extra-sensitive to small disruptions in that machinery.

Fortunately, in recent years, chemical compounds have been developed that are capable of blocking certain proteins that make up the transcriptional machinery; these compounds are called transcriptional cyclin dependent kinase (CDK) inhibitors. And some have just recently started to enter clinical trials. When tested in other cancers that exhibit the same pattern of addiction to a transcription factor like brachyury, these compounds have demonstrated significant antitumor activity.

Which brings us to the third approach to discover new targets: testing a library of more than 450 chemical inhibitors of known cancer targets against chordoma cell lines. With a hunch about being able to exploit chordoma’s addiction to brachyury with transcriptional CDK inhibitors, the Broad team obtained several such inhibitors from labs around the world to include in their tests.

Sure enough, several of these transcriptional CDK inhibitors turned out not only to shut off brachyury but to be among the most potent of any of the compounds tested. And, when they tested one of these compounds, called THZ1, in a mouse model of chordoma, they found that it was able to dramatically slow the growth of the tumors. THZ1 is what’s called a “tool compound,” meaning that it’s suitable for laboratory experiments but doesn’t have the properties that would make it suitable as a drug for use in humans. However, compounds similar to THZ1 are being developed into drugs by several pharmaceutical companies.

Possible new treatment option

Taken together, these findings provide strong rationale for exploring transcriptional CDK inhibitors as a treatment option for chordoma.

As a next step, we are working to obtain transcriptional CDK inhibitors that are currently in or approaching clinical trials so that we can test them in additional chordoma mouse models through our Drug Screening Program. If results are as promising, our hope would be to support a clinical trial with one of these drugs for chordoma patients in the next 1-2 years.

In parallel, we also need to continue investing in research to develop direct inhibitors of brachyury which may ultimately be required to sufficiently counter its effect in chordoma cells – either alone or in combination with a transcriptional CDK inhibitor.

The bottom line is that we now have a promising new therapeutic avenue to pursue that indirectly targets the Achilles’ heel of chordoma. This is an exciting milestone in the quest for better treatments, and a big win for all involved in the research. Huge thanks to the entire research team for the energy, dedication, brainpower and collaborative spirit they brought to this project. And much gratitude to everyone whose contributions have made and continue to make all this work possible!

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