Chordoma Foundation

Top 10 Takeaways from the Fifth International Chordoma Research Workshop

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On July 14-15, 115 researchers from 11 countries and 56 institutions came together in Boston for the Fifth International Chordoma Research Workshop. By far our best attended and most constructive research meeting yet, it featured presentations and perspectives from 32 of the world’s foremost experts in chordoma treatment and research, as well as scientists from a breadth of fields in academia and industry. Sessions focused on topics ranging from the state of the art in chordoma care to the latest on pathogenesis of the disease to therapy development and beyond. Moreover, vibrant group discussions throughout the two-day meeting provided an opportunity to advance our collective understanding of the disease, and to identify important new questions, hypotheses and lines of research to pursue.

Beyond providing a forum for exchanging the latest findings and ideas, this workshop served as an entry point to the chordoma research community for nearly 70 first time participants, and helped to strengthen ties among a growing network of collaborating labs across the world. Examples of collaborations resulting from relationships forged at prior workshops were borne out in presentation after presentation, and numerous new collaborations were sparked in hallway and dinner conversations between participants.

From this gathering of the world’s foremost chordoma experts, along with bright minds from a variety of related fields, emerged a number of important themes and imperatives that will shape the future of chordoma research and guide the Foundation’s upcoming research plans. Here are the top 10 takeaways that emerged from this year’s workshop:

  1. Surgery and radiation techniques are improving, but their use needs to be optimized.

Surgery and radiation continue to be the mainstays of chordoma treatment, and, when applied by experienced treatment teams, can be curative for many patients, but not all. Traditionally, radiation has been performed following a surgical resection; however, recent findings have raised questions about the optimal sequence of treatment, with some groups advocating for radiation both pre- and post-surgery. Moreover, evidence suggests that for certain patients with sacral tumors, radiation alone may be equally effective as surgery with less morbidity, but this has never been demonstrated through a controlled study and thus remains an open question. To address this question, the SACRO trial, a randomized prospective study comparing radiation vs. surgery for treating sacral chordomas, is getting underway in Europe later this year, designed to establish conclusively the optimal treatment for sacral chordoma patients. Importantly, the SACRO study will not only seek to determine the best treatment approach for controlling the disease, but which gives patients the best quality of life. This reflects a theme which ran throughout the workshop that we need to better understand the effects of existing treatment modalities on patient quality of life and do more to minimize their impact. For example, by providing a portion of radiation preoperatively, a lower total radiation dose may be suitable, thereby potentially reducing radiation-associated morbidity; however, further data is needed to support this hypothesis.

  1. New genes linked to chordoma susceptibility.

Through their ongoing Chordoma Genetics Study, Rose Yang and colleagues at the National Cancer Institute Genetic Epidemiology Branch have identified germline alterations in several patients with sporadic chordoma in two genes not previously associated with chordoma: BRCA2 and PALB2. Though only in small numbers of patients, these findings are interesting because BRCA2 and PALB2 are known to interact and both are associated with predisposition to other cancers, namely breast cancer, suggesting that they may be a part of the cellular process involved in chordoma pathogenesis. Remarkably, Ernest Radovani from Jack Greenblatt’s Lab at the University of Toronto also reported for the first time that BRCA2 is one of only a handful of proteins that bind to brachyury, raising the question of whether BRCA2 (and possibly PALB2) could somehow be involved in mediating brachyury function in chordoma. Further research is needed to determine the role of BRCA2 and PABL2 in chordoma, and whether this could point to a vulnerability that could be exploited for therapeutic benefit.

  1. The genomic landscape of chordoma is becoming more clear and it appears to be quiet but heterogeneous.

Whole exome and whole genome sequencing conducted by several groups have not revealed any highly recurrent driving mutations. What’s more, Patrick Tarpey from the Sanger Institute reported that most, but not all, chordomas appear to have a low mutation rate relative to most other cancers, and the pattern of mutations appears to be consistent with cancers due to age rather than external mutagenesis or DNA repair defects. Tarpey’s group and others found low frequency alterations in genes involved in histone modification, the PI3-kinase pathway, CDKN2a, and brachyury, indicating there may be a number of distinct genetic paths to develop chordoma. The one commonality across all cases of chordoma thus far appears to be overexpression of the brachyury protein. This, combined with mutations in multiple histone modifiers and few other obvious driver mutations, raises questions about the role of epigenetic events in chordoma pathogenesis, and demands further research into the epigenetic landscape of chordoma.

  1. Rapid progress in new model development is accelerating the pace of discovery. 

Since the last research workshop, major progress has been made in the creation of disease models. The number of validated cell lines has increased from three to 12, with over 20 more in development. Five of these lines are now available through the Chordoma Foundation’s cell line collection ATCC and have been shared with over 100 labs across the world, enabling many of the research projects presented at the workshop. Additionally, at least five patient derived xenograft models now exist, up from just one in 2013, with 22 more currently in varying stages of development. The Chordoma Foundation has recently established a panel of chordoma xenograft models at the contract lab START and is making them available for in-vivo experiments through its new Drug Screening Pipeline. With these new models now available, there was agreement that they need to be rigorously characterized to determine which molecular subsets of the disease they represent. Meanwhile, encouraging progress is also being made towards developing genetically engineered mouse and zebrafish models of chordoma, which could be useful for understanding the process of chordoma development, and as tools for drug screening. Notably, Mike Kelley and colleagues at Duke University have succeeded in developing what appears to be the first genetically engineered mouse model of chordoma, but further characterization and optimization of this model is needed.

  1. Immunotherapy may be promising if resistance mechanisms can be overcome.

Immunotherapy is showing tremendous promise in other cancers, but its potential utility for chordoma remains unclear. Chris Heery from the NCI presented data from clinical trials with two therapeutic vaccines targeting brachyury, both of which induced an immune response to brachyury in chordoma patients, and demonstrated promising signals of potential antitumor activity in some patients. Mike Lim from Johns Hopkins showed that chordomas commonly express the checkpoint molecule PD-L1, indicating the presence of a T cell response in many chordoma tumors, and suggesting that checkpoint blockade may enable therapeutic antitumor immunity. However, data presented by Soldano Ferrone from MGH indicates that many chordomas have defects in the antigen processing machinery required for T cell recognition, suggesting a possible mechanism of resistance to T cell killing. What’s more, because of the low mutation rate identified in chordoma, there may be few neoantigens present on chordoma cells that could trigger a T cell response. These obstacles may be overcome with radiation, which has been shown in other tumor types to enhance antigen presentation and immunogenicity. Supporting this hypothesis, Jim Hodge from the NCI showed that radiation significantly increases T cell mediated lysis of chordoma cells in-vitro. Moreover, preliminary data from the NCI suggests that methods to recruit natural killer cells may well induce antitumor immunity even in the presence of antigen presentation defects. Further research is needed to understand the chordoma-immune interaction and harness powerful new immunotherapy approaches.

  1. Multiple layers of evidence continue to converge on brachyury as the key driver and a prime vulnerability of chordoma.

Tanaz Sharifnia from Stuart Schreiber’s lab at the Broad Institute presented data from a genome-wide CRISPR loss of function screen, which identified brachyury to be the most essential gene for chordoma cell survival. Dr. Sharifnia also shared results from her collaboration with Charles Lin at Baylor College of Medicine mapping super-enhancer associated genes in chordoma cells, which revealed that chordomas consistently form a strong super-enhancer at the brachyury locus. Taken together, the results from these two unbiased approaches provide the strongest evidence yet that brachyury is central to the identity and survival of chordoma cells, confirming and building upon prior evidence generated in other labs. Additionally, more germline and somatic alterations in brachyury were reported by Patrick Tarpey from the Sanger Institute and Rose Yang from the NCI. Finally, the Kelley lab’s new genetically engineered mouse model generated by over-expressing brachyury in the mouse notochord provides proof positive that brachyury can drive chordoma pathogenesis.

  1. The search is on for approaches to target brachyury, and this is starting to become more feasible.

Given the essentiality of brachyury for chordoma cell survival, there is broad agreement in the research community that finding therapeutic interventions that can target brachyury is of utmost importance. What’s more, Duane Hamilton from the NCI laid out a compelling case for brachyury as a promising therapeutic target for many epithelial tumors in which it is believed to mediate metastasis and confer resistance both to cytotoxic therapies and T cell killing. As a transcription factor, conventional wisdom dictates that brachyury is a challenging drug target. But participants at the research workshop are not deterred and are tackling this challenge head on. For example, Nathanael Gray of Dana Farber laid out an innovative approach to suppress super-enhancer driven master transcription factors like brachyury by targeting components of the transcriptional machinery needed for their production, namely transcriptional cyclin dependent kinases (CDK’s). Testing this approach, Dr. Sharifnia demonstrated that indeed inhibiting transcriptional CDK’s with a small molecule developed by Dr. Gray dramatically reduces brachyury protein levels and is highly potent to chordoma cells. Meanwhile, Dr. Radovani identified several brachyury binding proteins which could potentially be targeted to disrupt brachyury activity, either by preventing its nuclear localization or by inhibiting the function of its transcriptional coregulators. Another idea proposed was to develop a small molecule “degronimid” that would bind both to brachyury and ubiquitin ligase thereby causing ubiquitination of brachyury and subsequent proteosomal degradation. In short, there are many technologies and approaches that could be employed to target brachyury which deserve further research and development.

  1. More new clinical trials are coming.

Significant advances in chordoma research over the past 9 years combined with newly developed classes of drugs and an increasingly energized and focused chordoma research community are culminating in a wave of new clinical trials. Well-justified plans for five forthcoming trials were presented at the workshop, including trials testing the EGFR inhibitor afatinib, the CDK4/6 inhibitor palbociclib, the PD-1 inhibitor nivolumab in combination with hypofractionated radiation, the hypoxia dependent oncolytic bacteria C. Novyi, as well as a randomized study comparing the effectiveness of surgery vs radiation for primary sacral chordomas (to learn about currently open clinical trials visit our clinical trials page, or contact our patient navigator at support@chordoma.org). These trials are being designed not only to look for signals of antitumor activity, but also to learn much more about the disease; for example, to identify biological predictors of response and to assess how the therapies affect patient quality of life. The Chordoma Foundation is partnering with the investigators running each trial to raise awareness among patients and treating physicians, and is planning to provide financial support for two of them in the coming year (see here). Looking ahead, as more promising therapeutic approaches are identified in the lab, the number of clinical trial opportunities is sure to continue growing in the years ahead. Various ideas were proposed to lower the barriers to starting these trials and increase their speed and efficiency. In particular, multiple participants called for a clinical research consortium through which active trial sites could work together to run multiple trials under common protocols and with shared infrastructure. This is an idea that has previously been endorsed by the Foundation’s Medical Advisory Board, but requires a sustained investment of capital which has not yet been available.

  1. New technologies could transform how chordoma is treated.

The workshop was capped by two fascinating talks exploring new frontiers in chordoma research. Kim Luddy from the Integrated Mathematical Oncology group at Moffitt Cancer Center demonstrated how competition among subpopulations of drug sensitive and drug resistant cells within various tumor types could be modeled mathematically, thereby enabling drug dose and schedule to be optimized to enhance and prolong tumor control. Counterintuitively, the models revealed that lower, intermittent dosing would produce far more sustained responses compared with higher continuous dosing, and this was indeed the case in mouse models. These findings are a reminder that dosing optimization is an important consideration in forthcoming in-vivo experiments and clinical trials for chordoma. Additionally, Chetan Bettegowda from Johns Hopkins showed that circulating tumor DNA could be detected in the blood of most chordoma patients, demonstrating the possibility of liquid biopsy technology to one day be used to monitor disease progression. Both approaches hold potential to change the way chordoma is treated and are examples of the value of the workshop for bringing new ideas into the field.

  1. Vibrant, interconnected research community continues to grow.

Since our last workshop three years ago, the community of researchers working on chordoma has expanded dramatically. More and more research teams are entering the field, evidenced by the nearly 70 first time participants representing institutions from San Francisco to Beijing to Zurich. And, notably, representatives from five pharmaceutical companies were present, reflecting increasing opportunity to bring effective therapies to market for chordoma patients. But beyond simply growing in size, the research community has grown closer and more collaborative. Throughout the workshop, we heard example after example of researchers teaming up to accomplish what none could do alone: MGH and the Broad Institute working together to identify chordoma’s vulnerabilities, UCL and UNC working together to screen libraries of novel kinase inhibitors, Johns Hopkins and Sloan Kettering working together to launch a new clinical trial. And, with each subsequent workshop new relationships form, which seed future collaborations and fuel continued momentum in the field. We feel confident that the bonds forged this year in Boston will continue to bear fruit over the coming years, and we appreciate the openness and constructive contributions of all who participated. Stay tuned for more exciting progress from this vibrant community.

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