We recently held our biennial International Chordoma Research Workshop (ICRW) — shifted online this year due to the pandemic — where there were some meaningful advances discussed and I wanted to take a moment to share highlights and key takeaways.
As background, this was the seventh research workshop we’ve held since 2007. The purpose of these gatherings is multi-fold: to enable rapid exchange of unpublished data, to surface new research ideas and opportunities, and to facilitate coordination and collaboration among researchers.
A silver lining of holding the event online was that it enabled many more investigators to participate: in total, 320 from 25 countries. That’s more than twice the number we’ve ever had in person and six times the number at the first workshop 13 years ago. It’s really heartening to see the field continuing to grow and to see the level of dedication and significant intellectual investment in our disease by so many talented physicians and scientists.
As a result of the collective efforts of this research community, progress toward a better understanding of the disease and better treatments continues to snowball, and that was very much evident at this year’s workshop. Below are some of the most notable takeaways that have the potential to influence patient care and treatment development.
Genetic alterations in chordomas point to possible therapeutic options in some patients.
Recent genomic studies have provided further evidence that chordomas often have mutations in the therapeutically relevant genes CDKN2A, MTAP, and various genes involved in cellular machinery that regulates how DNA is packaged called the SWI/SNF complex. Preclinical and clinical research on therapies that exploit all of these alterations is ongoing or planned. Several new, uncommon mutations which could help guide the care of individual patients were also reported which bear further investigation.
There is a molecular signature for rapidly progressing chordomas.
A molecular signature has been identified in certain clival chordomas that behave very aggressively. Though still preliminary, in the not too distant future this could possibly help determine a patient’s prognosis, guide treatment decisions, and possibly point to new therapeutic targets for biologically aggressive chordomas. Further work is planned to explore whether this finding applies to chordomas of other anatomic locations.
The stage has been set for development of drugs targeting brachyury.
Various research teams have together developed the full complement of materials and analytic tools needed to evaluate and optimize compounds created to target brachyury. These resources are available to any research group or company that wishes to pursue development of brachyury drugs. Moreover, with this experimental pipeline in place, researchers supported jointly by the Chordoma Foundation and the Mark Foundation for Cancer Research, are racing ahead on medicinal chemistry to create open access “tool compounds” that target brachyury in cells, and which could be optimized into drug candidates suitable for clinical trials.
The yeast brachyury vaccine GI-6301 with radiation is not more effective than radiation alone.
While anecdotal responses on a phase 1 trial generated much excitement about this therapy, early results of a randomized phase 2 trial testing radiation alone vs. radiation plus GI-6301 showed no significant difference in responses between the two treatments, leading the trial to be ended early. This is a disappointing outcome for a treatment that seemed so promising and a sobering reminder that we have much more to learn about how to most effectively unleash an immune response to chordoma. However, a negative result from this trial does not diminish the significant potential in targeting brachyury with other types of vaccines (e.g., viral vs. yeast-based vaccines) as well as combining vaccines with other immunotherapies such as checkpoint inhibitors. The results of this trial also have no bearing on the utility of other types of (non-immune) therapies that target brachyury directly.
Several encouraging drug responses were reported.
We heard a case report about a patient who had a dramatic response to palbociclib (which is currently being tested in a clinical trial for chordoma). We also heard about three patients whose tumors responded to pemetrexed on an ongoing trial.
Multiple new targets and promising drugs have been identified.
Researchers from several universities have identified drugs that are showing significant activity in cell and/or mouse models of chordomas. Some have been added to the queue for testing through the Foundation’s Drug Screening Program, while others may be ready to move into clinical trials.
The groundwork is being laid for cell based immunotherapy.
Preliminary data is emerging which points to several potential targets for cell based immunotherapies — therapies that utilize patients’ immune cells to fight cancer. These findings could be translated into new therapies that have the potential to reach clinical trials within the next two to three years.
Studies are getting underway to track outcomes of chordoma patients.
One is a retrospective study spearheaded by a group of radiation oncologists which is focused on defining outcomes for patients treated with radiation. This will serve as a baseline against which new forms of radiation and/or radiation sensitizers could be compared in future clinical trials. Another is a comprehensive natural history study being conducted by the National Cancer Institute’s Rare Tumors Initiative which serves multiple purposes: to identify factors associated with patient outcomes, to spot trends in treatments that help or don’t help chordoma patients, and to generate ideas about new therapeutic approaches, and to establish a baseline against which the effect of new therapies can be compared. A key outcome of the workshop was agreement among these groups as well as others conducting observational studies to coordinate efforts and harmonize data collection.
Additionally, discussion at the workshop as well as a follow-up survey we conducted of workshop participants highlighted and reaffirmed key priorities going forward, including:
In addition to a continued focus on developing drugs to target brachyury, participants emphasized the need to continue studying how brachyury functions within chordoma and other cancers.
New therapeutic targets
While many lines of evidence have pointed to brachyury as the greatest vulnerability of chordoma, continuing to identify other targets that may be therapeutically significant is important for maximizing the chances of identifying effective treatments. There is particular interest in identifying epigenetic drivers of chordoma and identifying drug combinations that are more effective than one drug alone.
Much remains to be learned about how chordoma interacts with the immune system in order to determine which types of immunotherapy are relevant to chordoma. For this to happen, there is more that we need to do to continue attracting top immunotherapy researchers to turn attention to chordoma.
Predictive and prognostic biomarkers
Emerging evidence suggests that there are molecular signatures that may make it possible to tailor treatment to individual patients, and to determine which patients are likely to be cured with standard treatments versus which will progress and require further therapy. These biomarkers need to be validated and then incorporated into treatment protocols.
Streamlining clinical trials
The way that clinical trials are done needs to be improved to make it feasible to efficiently test all of the promising new treatment approaches that are emerging. Recommendations include (1) developing ways to measure tumor response that are more tailored to chordoma than the standard measurement criteria, (2) establishing a clinical trials network that can quickly initiate and enroll patients onto trials, and (3) launching a “platform trial” in which multiple different treatments would be compared in parallel against a single control treatment group.
In recent years, several research groups have generated large molecular data sets, which have the potential to yield additional insights if combined and analyzed together. Moreover, all these data sets should be easily accessible to the broader research community to enable more researchers to explore them from different angles. We need to invest in bringing all existing data sets into the Foundation’s Data Repository.
Certainly, much work remains to be done, but it’s thrilling to now have so many viable paths to better treatments in the short, medium, and long term. I look forward to keeping you posted as progress continues, and, meanwhile, welcome any questions or ideas.