Whenever a gene is found to cause an inherited disease, researchers naturally wonder whether changes in that same gene could play a role in the non-inherited (sporadic) version of that disease as well. So when familial chordoma (an extremely rare disease) was found, in 2009, to be caused by inheriting extra copies of a gene called brachyury, the entire chordoma research community pondered whether brachyury was responsible for driving sporadic chordomas as well, and, speculated that it could be a potential therapeutic target.

In a paper to be published in February in the Journal of Pathology, a team of researchers at University College London (UCL) – Cancer Institute, and the Royal National Orthopaedic Hospital, Stanmore, UK led by Dr. Adrienne Flanagan and Dr. Roberto Tirabosco and supported by their clinical colleagues at the London Sarcoma Service, report that brachyury is amplified (present with more than the expected two copies) in about 50% of sporadic chordomas. This provides the first strong evidence to support the idea that sporadic chordomas are driven by brachyury, since amplification of a gene often means that it is giving the cancer cells an advantage.

In 2006, Dr. Flanagan and her colleagues first discovered that brachyury is highly expressed in virtually all chordomas, and, since then, brachyury has become the definitive marker used to differentiate chordomas from other similar tumors such as chondrosarcomas. However, just because a gene is highly expressed does not mean that it is driving a tumor. Nevertheless, because brachyury is known to play an important role in the development and survival of notochord – the tissue from which chordoma arises – there was talk at the First and Second International Chordoma Research Workshops about trying to shut down brachyury in chordoma cells as a way to stop their growth.

Now, for the first time, the UCL researchers have done just that. Using RNA interference – a relatively new technique which can turn off individual genes one a time – they reduced the expression of brachyury in a chordoma cell line by 97%. And, just as predicted, the cells stopped growing.

Taken together these findings suggest that brachyury plays an important role in the development and survival of chordoma. This implies that treatments/drugs that inhibit brachyury function could stop the growth of chordomas. Further research is now needed to determine whether knocking down brachyury can shrink tumors in animal models. Because treatments based on RNA interference are not yet available in the clinic, researchers have already embarked on an effort to find other means of targeting brachyury – both through immune therapy and with chemical compounds, suitable for turning into drugs. Though these treatment development efforts will be a significant undertaking, thanks to these recent discoveries, there is now sufficient evidence to justify this investment.