In March of 2018, 140 doctors and scientists from more than ten countries and 70 institutions braved a nor’easter to come together in Boston for the Sixth International Chordoma Research Workshop (ICRW) where they shared learnings, exchanged ideas, and forged the partnerships needed to bring a wave of new discoveries from the lab to the clinic.
Sessions topics ranged from state of the art clinical management to the latest in target discovery and therapeutic development and featured research findings and ideas from a wide range of experts and disciplines. The overwhelming consensus from our largest and most diverse group of participants yet was that scientific progress is starting to have a real impact on the lives of chordoma patients bringing better treatments within reach.
After a decade of foundational research, our community is now defining targets that are appealing to drug companies, embarking on clinical trials that show promise, and even seeing some encouraging responses to experimental therapies. And more and more talented scientists and clinicians from around the world are joining the cause and helping to shape the future of chordoma treatment and care.
Here are the top 10 takeaways that emerged from this year’s workshop, and will shape the Foundation’s research plans moving forward:
1. Efforts to target brachyury, the “Achilles heel” of chordoma, are in full swing.
|Panel discussion: The role of radiotherapy in the management of chordoma|
There is now strong evidence that the transcription factor brachyury, a protein encoded by the T gene, is the key driver and a major vulnerability in chordoma. Brachyury is also implicated in disease progression, metastasis, and resistance to therapy in several other cancers, including breast, lung, colon, and prostate cancers. Brachyury is highly expressed in almost all chordoma tumors and is essential for the survival of chordoma cells. Given its potential as a key therapeutic target for chordoma, brachyury drug discovery is now a top investment priority for the Foundation, and the focus of several ongoing research projects and clinical trials. Many labs within the research community have already laid the groundwork and are driving these efforts forward, utilizing different approaches to target and inhibit brachyury including 1) interfering with upstream events that lead to the production of brachyury; 2) interfering with brachyury function; 3) inhibiting brachyury-dependent downstream events; and 4) identifying ways to directly degrade brachyury. And a new funding opportunity, the Therapeutic Innovation Award, issued in collaboration with The Mark Foundation for Cancer Research earlier this year, aims to capitalize on emerging technologies that can speed the discovery of therapies targeting A gene that makes a protein, also called brachyury, that is present at high levels in nearly all chordoma tumors.. The collective impact of these efforts will, we believe, lead to the creation of the first drugs capable of targeting brachyury and benefit not only chordoma patients but also a much broader group of cancer patients.
2. There is both progress and promise in the quest to apply advances in immunotherapy to chordoma.
In recent years, there have been major leaps forward in the ability to harness the power of an individual’s immune system to fight their disease, which has proven to be successful in treating certain types of cancers such as melanoma and lung cancer. As we learn more about the ability of immune cells to attack chordoma cells, there appear to be defects in the antigen processing machinery (APM) which decreases the capacity of T-cells to kill chordoma cells. Radiotherapy has been speculated to modulate the APM allowing better antigen presentation leading to enhanced T cell killing of tumor cells. At the meeting, preclinical data was presented that showed the synergistic effects of combining radiotherapy and Systemic therapies that are designed to teach the immune system how to find and destroy cancer cells. on reducing tumor growth using a humanized mouse model. Two clinical trials are now open specifically to chordoma patients incorporating radiotherapy in combination with either a vaccine against brachyury or the immune checkpoint inhibitor, nivolumab. During an immune breakout session at the conference, participants explored various combination approaches that have the potential to improve effectiveness and combat resistance. In addition, and of paramount importance, was the suggestion to analyze the patient’s immune cell repertoire prior to treatment to determine immune correlates of response to different therapeutics. Based on encouraging results in this field and opportunities to apply findings from other cancers to chordoma, the Foundation is developing a strategic research plan to direct future investments into chordoma Systemic therapies that are designed to teach the immune system how to find and destroy cancer cells..
3. Several new clinical trials are enrolling chordoma patients, and more are on the way.
Historically, treatment options for patients with residual, recurrent, or advanced chordoma have been limited and inadequate. In the past two years opportunities to explore evaluation of promising therapies in trials specifically designed for chordoma patients have increased. Currently, our Clinical Trials Program includes a pipeline of seven chordoma-specific trials, three of which are already enrolling patients. Some test the immune therapeutic approaches described above and others test targeted agents which have been identified in part through the Foundation’s preclinical resources and Drug Screening Program as well as research conducted in various laboratories worldwide. Additionally, more than a dozen chordoma-relevant trials (trials enrolling multiple tumor types including chordoma) are already underway. In light of the availability of these trials, our Medical Advisory Board (MAB) recommends patients with advanced or recurrent chordoma consider a chordoma-specific Research studies involving human subjects that are done to test whether a treatment is safe, and how well it will work to treat a specific disease. or chordoma-relevant clinical trial before turning to the The practice of prescribing drug treatments that are not approved by government agencies to treat a particular disease. Doctors are allowed to prescribe drugs off-label if they believe it is in the best interest of the patient. use of therapy.
4. There is a growing demand to further define chordoma treatment protocols by subtype and anatomical locations.
Workshop participants agreed that one of the biggest upcoming challenges in chordoma treatment will be developing protocols specific to each of the four histologic subtypes of the disease – conventional, One of the four histological types of chordoma, this term was more commonly used in the past when it was difficult to tell the difference between conventional chordoma and chondrosarcoma. Chondroid chordomas behave similarly to and are treated the same as conventional chordomas. , de-differentiated, and A histological subtype of chordoma that is more aggressive and usually grows faster than the conventional type. It is more common in children and young adults, and is often characterized by loss of the INI1 protein. – as well as management of the disease depending on anatomical locations. While the function and value of molecular profiling in this effort was the source of discussion and debate, many agreed a true longitudinal protocol should be pursued to collect uniform data and samples for profiling over the course of a patient’s journey with chordoma. This type of study would require large numbers of patients representing the different histological and anatomical types of chordoma as well as coordination across multiple centers. Given our role as a convener, there was a sense that the Foundation could help to facilitate this effort, working with the research community to drive consensus and engagement. The resulting dataset, participants agreed, would help to inform and drive future disease management decisions in an era of emerging drug therapies.
5. A strong emphasis on better understanding and managing pediatric chordoma emerged.
While chordoma research and support services have advanced significantly in the past decade, progress for the pediatric subset of the patient population has lagged. Making up fewer than 10 percent of chordoma cases, pediatric chordoma poses a special set of challenges for research, patient care, and the families of children who are affected. These challenges were the focus of a special session on pediatric chordoma led by Dr. Brigitte Widemann, Chief of the Pediatric Oncology Branch at the National Cancer Institute. Participants discussed the unique characteristics of pediatric chordoma, including its distinctive radiology features, clinical aggressiveness, and propensity to metastasize, and the possibility of categorizing pediatric chordoma as its own histologic subtype with its own treatment protocols. Also emphasized was the importance of taking a multi-disciplinary treatment approach for pediatric patients and ensuring they receive treatment from providers familiar with pediatric chordoma at centers equipped to address the specific needs of pediatric patients. Shortly following the conference, the Foundation announced the launch of a multi-year, $1.5 million Pediatric Chordoma Initiative designed to accelerate the development of better treatments and support services for pediatric patients and their families. Seeded with generous contributions totaling $1.3 million from three families of young children with chordoma, it begins to tackle many of the issues discussed at the meeting and reflects the Foundation’s overarching commitment to ensure that all chordoma patients benefit from advances in research.
6. Progress is being made in the clinical management of chordoma, with significant advances in surgical and radiation treatments.
Surgery and radiation still represent the mainstays of chordoma treatment even as the debate continues over the ideal timing of radiation – prior to surgery versus post-surgery. At the meeting, data was presented supporting the benefit of pre-operative radiation in certain clinical situations. A greater use of scanning proton beam therapy and now radiation using carbon ions is being offered by centers who have these capabilities, and a comparison on patient outcome between the two types of radiation treatment needs to be performed. Evidence continues to suggest that in certain patients with sacral tumors radiation alone may be equally effective as surgery with less morbidity. To address this latter point, two years ago at the 2016 ICRW meeting the S.A.C.R.O trial design was presented. This is a randomized prospective study comparing surgery vs. radiation in the treatment of sacral chordoma patients that is being conducted in Europe and ultimately extended to additional non-European countries. Since then, the S.A.C.R.O trial has opened and at the time of this meeting, patients have been enrolled in the study. Patient-reported The health condition of a person after being diagnosed and treated for a particular disease. Outcome is usually measured at different time points. For example: one-, five-, or ten-year outcome. measures are an integral component of this study to fully assess the impact of current treatment modalities on quality of life.
7. The chordoma community must come together to identify and define appropriate clinical endpoints with the incorporation of patient-reported outcomes and quality of life assessments.
One of the key concerns raised by the research community was the current lack of a systematic approach to surveillance, creating a need to develop uniform guidelines for imaging by primary disease site. In addition, participants called for more sensitive response and progression criteria that take into account the site of primary disease. One potential solution that was widely championed onsite was the creation of a well-documented natural history study of chordoma. The challenge to building such a study, at present, is the absence of a unified data collection process across the many institutions involved. Retrospective data collected thus far may not provide the uniformity needed to learn about the natural history of the disease leading researchers to consider other opportunities to collect this critical data in a uniform manner. A key theme raised in the clinical endpoint discussion was the desire to explore the use of patient-reported outcomes (PRO) in the assessment of the disease. Various PROs have been developed in chordoma that are specific to the primary site of the tumor – so groundwork has been established – but moving forward it will be important to ensure the objectivity of these measurements. Participants discussed the merits of engaging patients in determining the most critical items to measure, aiding in the identification of clinically important endpoints that are patient defined and clinician confirmed.
8. Important new players are entering the field of chordoma, bringing their diverse expertise to bear on behalf of patients.
|Dr. Adam Resnick, Director of the Center for Data-Driven Discovery in Biomedicine at the Children’s Hospital of Philadelphia|
Since our last research workshop in 2016, the Foundation has continued to seek and establish meaningful partnerships with a growing number of organizations and experts from outside the field of chordoma, many of whom were represented on site. For example, The Mark Foundation for Cancer Research (MFCR) was on-hand to support our co-issued Therapeutic Innovation Award, aimed at the accelerating the development of drug therapies targeting brachyury. And in a special session on “Opportunities to accelerate chordoma research”, Dr. Adam Resnick, Director of the Center for Data-Driven Discovery in Biomedicine (D3b) at the Children’s Hospital of Philadelphia (CHOP) discussed the Foundation’s recently initiated collaboration with CHOP, establishing it as the official coordinating center for the Chordoma Foundation Biobank. One of the most exciting aspects of this collaboration is that in addition to streamlining our biospecimen collection, management, and distribution, it will also provide chordoma investigators with access to centralized, web-based research and informatics platforms through which they can ask specific questions in real-time and build customized data sets to study. CHOP’s cloud-based genomic platform, Cavatica, not only hosts chordoma data but also includes datasets from other pediatric and rare cancers allowing researchers to access information across multiple disease types, accelerating translational research. Additional talks in this session focused on opportunities to collaborate with other leading organizations and institutions on everything from the study of pediatric chordoma to the development of registries that could help define clinically relevant endpoints and lead to a better understanding of the natural history of the disease.
9. One of the biggest challenges/opportunities ahead is finding a way to increase the pace of knowledge sharing within the CF research community between ICRW meetings.
Given how quickly the chordoma research community has grown, and how widespread it is in both geography and discipline, it is understandable that the demand for real-time information sharing across the network is on the rise. Timely data sharing across chordoma research centers between and beyond the International Chordoma Research Workshop, which takes places every two years, is of utmost importance, participants agreed. To address this need, participants proposed creating a unified database through which all chordoma research investigators and clinicians could access and deposit different types of data. This central repository would need to be built around a uniform set of standards to ensure that data and results are comparable. And, ideally, it would be overseen by a proactive coordinator who could compile the data and ensure that it is made publicly available in a timely manner. Pointing to other organizations such as the Structural Genomics Consortium as models for identifying creative ways to share data in real-time, participants encouraged the Foundation to explore solutions for advancing open science across the chordoma community.
10. Our research efforts are being held up as a model for other rare cancers to follow.
Since the Chordoma Foundation was established, we have been driven by the belief that success in enabling and accelerating research for chordoma would not only lead to the cure we seek but also inform new approaches for other rare cancers. Over the past year, chordoma’s “playbook” has begun to be touted as a model for other rare cancers to follow to alleviate research roadblocks, capitalize on cutting-edge technologies, and bring new treatments from theory to reality. And this theme was apparent throughout the conference, with an emphasis and excitement around the ways in which our research investments, in brachyury as an example, might yield new treatments whose benefit could extend beyond our own patient community.
Stay tuned for more exciting progress from this vibrant community! In the meantime, materials from the 2018 International Chordoma Research Workshop – including agenda, speaker abstracts, photos, and more – can be found here.