Adrienne Flanagan is a pathologist and professor at the University College London Cancer Institute. Her focus was not always on chordoma, but initially spanned a wide variety of bone and soft tissue cancer types (sarcoma). In 2005, she and her colleagues cataloged the gene expression profiles of various kinds of sarcomas, one of which was chordoma. And what they found, she says, led her to “kind of a light bulb moment.”
Flanagan’s group discovered that brachyury, a protein that is important during embryonic development, was expressed at unusually high levels in chordoma cells. This was unlike the other tumors the group profiled.
“Suddenly we had identified a chink in the armor of chordoma,” she explains. “We had something novel and interesting which we could take forward in research, and allow us to understand this rare disease.”
Since the group reported its findings, brachyury has become the gold standard marker for diagnosing chordoma, as well as a key target for treatment. In an ongoing clinical trial, for instance, the U.S. National Cancer Institute (NCI) is testing whether a therapeutic vaccine against brachyury will improve the effectiveness of radiation when treating chordoma.
The brachyury finding propelled Flanagan’s research into chordoma at a time when there were just a handful of researchers in the field, and little was known about the disease.
“If one wants to figure out how to control the disease, one needs to understand the signals and driving forces making it grow,” she says. “To achieve that, one has to look at the genetic alterations in the cells.”
In hopes of uncovering new ways of treating chordoma, Flanagan partnered with the Wellcome Trust Sanger Institute – one of the world’s leading DNA sequencing centers – on the “Chordoma Genome Project,” an ambitious initiative to characterize comprehensively the genetic changes that drive chordoma. With support from the Chordoma Foundation, Flanagan and her colleagues at the Sanger Institute have sequenced over 100 chordoma tumors, which has provided important insights into the genes and pathways that drive chordoma.
Most notably, in 2012, this research revealed that nearly all chordoma patients have an inherited alteration in at least one copy of the brachyury gene – an alteration that is necessary, but not by itself sufficient, for chordoma to develop. This important discovery has spurred labs across the world to work to understand how brachyury drives chordoma, and how it can be shut off within tumor cells.
Creating needed models
Translating these insights about the genetics of chordoma into new therapies requires laboratory models of the disease such as cell lines and mouse models for researchers to work with – resources that didn’t exist when Flanagan began studying chordoma.
In 2008, Flanagan was one of a handful of researchers the Chordoma Foundation called on to help overcome this problem. With a seed grant from the Foundation, Flanagan and colleagues worked hard to coax human chordoma cells to grow in mice, eventually succeeding in developing the first xenograft mouse model for chordoma. The resulting tumors that grew in mice appeared identical to those in humans. Now, this model is central to the Drug Screening Pipeline recently launched by the Chordoma Foundation, through which researchers have already been able to test over a dozen new treatments.
Additionally, Flanagan is one of the few researchers in the world who has successfully developed new chordoma cell lines. Rather than doing it alone, she established a partnership with experts at the University of Ulm, in Germany, who were the first to successfully develop a chordoma cell line. Flanagan provided tissue, while the Ulm group provided carefully developed protocols to keep the fickle cells alive in a petri dish. This partnership resulted in several new chordoma cell lines that were established in collaboration between the two institutions. What’s more, the Ulm group trained members of Flanagan’s lab on their techniques, thereby enabling Flanagan’s team to develop more lines in her lab in London.
This kind of collaboration among researchers is all too rare, yet Flanagan has proven – time and time again – that it can have significant benefits.
In another remarkable example of collaboration, Flanagan recently teamed up with researchers from GlaxoSmithKline, the pharmaceutical company, as well as academic researchers from Austria, Germany, and the UK (Cancer Research Technology). Their goal: to test over 1,000 compounds on seven chordoma cell lines. Funding for the screening was provided by Chordoma UK, a nonprofit started by one of Flanagan’s patients to support patients and fund research in the UK, along with Rosetrees Trust and Sarcoma UK. The results were heartening.
GlaxoSmithKline helped supply many of the compounds, the Chordoma Foundation supplied cell lines, and Flanagan worked with her fellow researchers in Cancer Research Technology and others to identify which compounds most effectively stopped chordoma cells from growing.
The group found that many compounds effectively killed chordoma cells. The compounds that were most effective worked by shutting down a protein called EGFR, which regulates cell growth, and, when switched on, causes cancer cells to grow and multiply uncontrollably.
This protein wasn’t new to Flanagan, however. In 2011, she first reported that EGFR inhibitors could stop chordoma cells from growing. But back then, she notes, there was only one chordoma cell line, and accessing compounds to test was not easy.
“The initiative that the Chordoma Foundation took to encourage researchers to generate cell lines was enterprising and imaginative. These models of disease – cell lines and mouse models of chordoma – are key to the development of new treatments, and are accelerating the entire research process.”
In fact, the results of the recent drug-screening study, along with those from other labs, were strong enough to justify a clinical trial scheduled for later this year, which will test an EGFR inhibitor called afatinib.
Collaboration has proven to be both fruitful and professionally satisfying, Flanagan says.
“The field is starting to see the payoff from working together, and together we’re starting to have a real impact in terms of embarking on new treatments from which patients should benefit,” she says.
Flanagan credits the Chordoma Foundation for making many of her accomplishments possible, both by providing funds for the work, and by generating worldwide momentum for chordoma research. CF, she noted, funded her work to develop xenograft mouse models and new cell lines, the latter of which allowed her group to research EGFR inhibitors. The Foundation, along with others, notably Chordoma UK, is also helping to fund the upcoming clinical trial on EGFR inhibitors.
The Foundation has also given her opportunities that provide meaning for her work beyond science, particularly at Chordoma Community Conferences.
“What makes the greatest impression on me is meeting the patients and their families,” she says, “and how they look out for each other. And how driven they are to beat the odds.”
And, she adds, this is also a reminder of her large responsibilities as a researcher.
“When you go to a regular scientific meeting, you don’t come away with that same feeling that you have a responsibility to deliver for others,” she says.
Adrienne Flanagan will be moderating a panel at the upcoming International Chordoma Research Workshop and sharing an update on research progress during the Chordoma Community Conference this Saturday, July 16.