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...
Brachyury Drug Discovery Initiative
Creating drugs that strike at the Achilles’ heel of chordoma
A large body of research points to brachyury as the key driver of chordoma, its most critical vulnerability, and its most promising drug target. Moreover, because brachyury is not present in normal human tissue, therapies targeting brachyury could, in principle, control chordoma without causing harm to patients. Yet, brachyury belongs to a class of proteins called transcription factors which have historically been considered difficult drug targets — often described as “undruggable.” Thankfully, a confluence of emerging technologies have the potential to overcome the barriers to drugging this important class of targets, and to put drugs against brachyury within reach. The goal of our Brachyury Drug Discovery Initiative is to bring every plausible technology to bear to make brachyury targeting therapies available to patients with chordoma and other cancers as quickly as possible.
Brachyury is a protein encoded by the TBXT gene — a gene that everyone has in every cell of their body. The brachyury protein is vitally important during embryonic development, and is normally switched off after birth. However, it gets turned back on in a variety of tumors including chordoma. In certain tumors such as breast, lung, colon, and prostate cancers, it contributes to metastasis, resistance to therapy, and poor outcomes. In chordomas, brachyury doesn’t only contribute to bad behavior; it is the key driver of the disease. Laboratory research has shown that shutting off brachyury in chordoma cells renders them incapable of proliferating and prone to death.
Strategy
In partnership with the Mark Foundation for Cancer Research, we are working to bring about the first therapies targeting brachyury by strategically initiating and investing in a portfolio of drug discovery projects pursuing a variety of therapeutic modalities. Initially, we are prioritizing development of targeted protein degraders and small molecule inhibitors, and at the same time exploring the feasibility of additional modalities such as RNA targeted small molecules, antisense oligonucleotides, DARPins, and others.
In parallel, we are investing in research to develop critical understanding of brachyury’s function, and to develop essential R&D enabling resources, including the tools needed to identify new drug candidates and test their effects on brachyury.
We are proud to partner with the Mark Foundation for Cancer Research to invest in research applying innovative approaches and technologies to brachyury drug discovery, which could serve as proof of concept for drugging other difficult targets.
Projects
| Phenotypic screen for inhibitors of brachyury function | Slim Sassi, PhD – Massachusetts General Hospital | Ongoing |
| Chemoproteomic based drug discovery | Dan Nomura, PhD – UC Berkeley | Ongoing |
| Abolishing brachyury function through degradation | Craig Crews, PhD – Yale | Ongoing |
| Structure-guided drug discovery for brachyury inhibitors | David Drewry, PhD – UNC Opher Gileadi, PhD – Oxford Paul Workman, PhD – ICR | Ongoing |
| Identifying and targeting brachyury transcriptional deregulation in chordoma | Charles Lin, PhD – Baylor College of Medicine | Complete |
News
The Chordoma Foundation and The Mark Foundation for Cancer Research fund open-source research to accelerate drug discovery following recent breakthroughs
The Chordoma Foundation (CF) and The Mark Foundation for Cancer Research (MFCR) announced today a two-year, $1.4M partnership with a team of researchers at three institutions to develop new treatments for chordoma, a rare and difficult-to-treat bone cancer. The...
New paper confirms that brachyury is the Achilles’ heel of chordoma, and reveals a new way to attack it
I’m 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...
Announcing three new investments to catalyze brachyury drug discovery
We are pleased to announce that the Chordoma Foundation and The Mark Foundation for Cancer Research (MFCR) have together awarded three new grants to support innovative research projects aimed at discovering the first drugs that target brachyury – a protein believed to...