Chordoma Foundation

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.

The Mark Foundation for Cancer Research

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

 Project

Principal Investigator(s)

Status

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

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...

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