How Scientists Are Targeting the "Undruggable" Brachyury Protein to Combat Chordoma
For the roughly one in a million people diagnosed with chordoma, treatment options have remained virtually nonexistent for decades. This rare bone cancer, which typically occurs along the spine or skull base, has frustrated oncologists and researchers alike with its resistance to conventional chemotherapy and radiation 8 .
The prognosis for patients with advanced chordoma remains poor, with median survival around six years and treatment primarily limited to surgery and radiation when possible 8 .
Surgery Effectiveness
Radiation Effectiveness
Chemotherapy Effectiveness
What makes this cancer particularly elusive is its genetic quietness—unlike many cancers with numerous targetable mutations, chordoma tumors present few clinically actionable genetic alterations 1 . For years, the scientific community faced a therapeutic dead-end—until researchers identified the cancer's Achilles' heel: a protein called brachyury.
"It was utterly frustrating. Thirty-six years ago, there was little we could do to treat chordoma."
Brachyury (from the Greek meaning "short tail") isn't a foreign invader but rather a protein everyone has in their body during embryonic development. It plays a vital role in forming the notochord, a precursor to the spinal column. Normally, the brachyury gene switches off after birth, but in chordoma, it mysteriously reactivates 9 .
The Chordoma Genome Project revealed that brachyury isn't just present in these tumors—it's fundamentally driving the disease, with more than 20% of sporadic chordomas actually acquiring extra copies of the brachyury gene .
Brachyury is what scientists call a transcription factor—a type of protein that acts like a master switch, controlling which genes are turned on or off in a cell. In chordoma, brachyury isn't merely present; the cancer cells become "addicted" to it 1 .
What adds to brachyury's appeal as a target is its absence from most normal adult tissues. This means therapies targeting brachyury could, in principle, control chordoma without causing widespread harm to patients—the holy grail of cancer treatment 9 .
The pivotal 2019 study published in Nature Medicine marked a turning point in chordoma research by systematically identifying the cancer's dependencies 1 . The research team, led by scientists from the Dana-Farber Cancer Institute and collaborating institutions, employed two complementary cutting-edge approaches to uncover chordoma's vulnerabilities.
The researchers designed their investigation with parallel strategies to ensure robust results:
Using the gene-editing technology CRISPR-Cas9, the team systematically disabled individual genes in two chordoma cell lines. They introduced a library of over 74,000 guide RNAs targeting approximately 18,560 genes, then observed which genetic edits proved fatal to the cancer cells 5 .
In parallel, the team tested 459 small molecules—including FDA-approved drugs, preclinical agents, and molecular probes—against four chordoma cell lines to identify compounds that effectively suppressed chordoma proliferation 5 .
The results were striking in their clarity. The CRISPR screening revealed that the top three selectively lethal genetic targets in chordoma cells all pointed to the same gene: T (the brachyury gene) 1 5 .
| Gene Target | Function | Effect of Inhibition | Selectivity |
|---|---|---|---|
| T (brachyury) | Developmental transcription factor | Profound reduction in cell viability; disruption of notochord identity | Highly selective for chordoma |
| CDK7 | Transcriptional cyclin-dependent kinase | Reduced proliferation & induction of apoptosis | Selective |
| CDK13 | Transcriptional cyclin-dependent kinase | Reduced proliferation & induction of apoptosis | Selective |
| CDK9 | Transcriptional cyclin-dependent kinase | Reduced proliferation & induction of apoptosis | Selective |
Further investigation revealed why brachyury is so vulnerable to transcriptional inhibition. The researchers found that the brachyury gene is associated with a massive 1.5-megabase genomic region containing "super-enhancers"—clusters of regulatory elements that drive high expression of genes critical for cell identity 1 5 .
| Compound | Primary Target | Observed Effect | Downstream Effect |
|---|---|---|---|
| THZ1 | CDK7/12/13 | Potent suppression of proliferation; apoptosis induction | Reduced phosphorylation of RNA polymerase II; decreased brachyury protein |
| Dinaciclib | CDK9 | Potent suppression of proliferation; apoptosis induction | Decreased brachyury protein |
| Alvocidib | CDK9 | Potent suppression of proliferation; apoptosis induction | Decreased brachyury protein |
| Various compounds | EGFR/ERBB2 | Suppression of proliferation | Previously reported effect in chordoma |
Chordoma research relies on specialized tools and models to unravel the disease's complexities and test potential therapies. Here are some key resources enabling progress in the field:
| Resource Category | Specific Examples | Function in Research |
|---|---|---|
| Cell Line Models | UM-Chor1, MUG-Chor1, U-CH2, CH-8, U-CH1 5 8 | In vitro systems for studying chordoma biology and testing drug candidates |
| Animal Models | Chordoma xenografts 1 | In vivo testing of drug efficacy and safety prior to human trials |
| Research Platforms | CRISPR-Cas9 screening 5 | Genome-scale identification of essential genes and vulnerabilities |
| Small-Molecule Libraries | 459-compound library 5 | High-throughput screening for potential therapeutic compounds |
| Analytical Techniques | RNA sequencing, Western blot, immunofluorescence 5 8 | Assessing gene expression, protein levels, and cell morphology |
The Chordoma Foundation has significantly advanced research by establishing a Drug Screening Program that allows any researcher or company to test promising drugs in validated chordoma models at a fraction of the usual time and cost 2 .
Drugs Tested to Date
More recently, the Foundation launched its own laboratory fully dedicated to chordoma research, further accelerating the pace of discovery 2 .
The discovery of brachyury addiction in chordoma and its vulnerability to transcriptional inhibition has opened multiple avenues for therapeutic development. Researchers are now pursuing various innovative strategies to target brachyury more directly and effectively.
"One part of the drug will bind to the target protein, while the other part engages directly with cells' waste disposal systems, which then degrades and flushes [brachyury] out of the cell," explained Professor Paul Workman, who is now leading efforts to develop such compounds 6 .
Advanced technologies like the Diamond Light Source synchrotron in Oxfordshire have enabled researchers to determine the 3D structure of brachyury in unprecedented detail, revealing several previously unknown sites on the protein's surface where drugs could potentially latch on 6 .
The Chordoma Foundation has launched a Brachyury Drug Discovery Initiative to bring every plausible technology to bear on developing brachyury-targeting therapies. The initiative is prioritizing multiple therapeutic modalities simultaneously:
Nature Medicine publishes breakthrough study identifying brachyury as chordoma's Achilles' heel 1 .
Chordoma Foundation establishes Brachyury Drug Discovery Initiative and dedicated research laboratory 2 9 .
Advanced structural analysis of brachyury protein reveals potential drug-binding sites 6 .
Human trials for brachyury-targeted therapies estimated to begin, with potential completion in approximately five years 6 .
"For patients facing this rare cancer, and for researchers like Workman who have personal connections to the disease, the progress represents more than scientific achievement—it's a race against time to transform frustration into hope, and to finally tame a cancer that has long been considered untamable."