Abstract
The Chordoma Foundation (CF) is a global nonprofit organization whose mission is to improve the lives of those affected by chordoma and lead the search for a cure. The Foundation’s goals are to bring about better treatments, better medical care, and a better experience for chordoma patients. To achieve those goals, CF strategically invests in chordoma research, works with providers to improve the care delivered to chordoma patients, and offers a suite of services to the chordoma patient community. Since 2007, CF has made significant progress in each of these areas, moving a wave of promising new treatments toward clinical trials and creating a more positive, supportive care experience for patients and their families.
Keywords
Chordoma, Healthcare improvement, Patient services, Research, Therapy development
Outline
Introduction 431
Organizational Profile 432
Goals 432
Better Treatments 432
Better Medical Care 432
Better Patient Experience 433
Programs and Services 433
Research 433
Uniting and Strengthening the Research Community 434
Investing in High-Impact Research 435
Resource Development 435
Target Discovery 437
Therapeutic Discovery 437
Preclinical Research 438
Clinical Research 438
Sharing Data and Biological Resources 439
Healthcare Improvement 440
Patient Services 441
Conclusion 442
References 442
Introduction
The Chordoma Foundation (“CF”) is a global nonprofit organization whose mission is to improve the lives of those affected by chordoma and lead the search for a cure. CF unites multiple stakeholders—patients, caregivers, doctors, scientists, drug developers, and others—to pursue a future in which everyone affected by chordoma is able to overcome the disease and maintain his or her quality of life.
CF was founded in 2007 by chordoma patients and families unwilling to accept inadequate treatment options and determined to improve the experience and odds of survival for individuals dealing with chordoma. At that time, chordoma was poorly understood and little research was being done to understand the disease or develop better therapies. Moreover, many patients struggled getting appropriate care and dealing with the myriad health effects and practical difficulties associated with the disease. With nowhere to turn for reliable information or support, many faced a bewildering, lonely, and perilous journey.
Since 2007, CF has helped catalyze efforts to address each of these issues. During that time, the nascent field of chordoma research has coalesced and come alive, resulting in a growing pipeline of promising new therapies, some of which are already in, or progressing toward, clinical trials. The first consensus guidelines for the diagnosis and treatment of chordoma were published to help ensure that more patients around the world receive high-quality, evidence-based care. And patients now have in CF a reliable source of information and support, with professional services and a community of peers to help them navigate every step of their journey.
This chapter provides an overview of CF, outlines its goals, and highlights programs that support patients, healthcare providers, and researchers in service of the organization’s mission.
Organizational Profile
The origin of the Chordoma Foundation dates to 2006 when a small group of chordoma survivors and family members motivated to improve the plight of those affected by chordoma connected through an online support group. Soon thereafter, several members of that group met at the annual conference of the National Organization for Rare Disorders. There, this group resolved to work together to create an organization dedicated to advancing the interests of chordoma patients everywhere. In February 2007, members of this group formed the Chordoma Foundation as a vehicle to organize and strategically channel the collective resources and efforts of everyone who desires a better future for those affected by chordoma.
The Chordoma Foundation is a 501(c)3 tax exempt organization incorporated in North Carolina. Though founded and headquartered in the United States, the Foundation’s mission and reach are global; it exists to serve the worldwide chordoma patient community and partners with healthcare providers, scientists, and companies around the world to advance research and improve patient care. CF views as its constituents not just chordoma patients, but everyone whose life is touched by chordoma, including family members, caregivers, and healthcare providers.
CF is governed by a Board of Directors comprising members of the chordoma patient community, as well as experts in relevant fields including law, finance, management, and medicine. Day-to-day operations and programmatic activities of CF are carried out by a professional staff with support from a host of volunteers across the globe. The staff and Board are counseled by three advisory boards—Medical, Scientific, and Community. The Medical Advisory Board (MAB) is comprised of leading physicians representing each of the primary specialties involved in caring for chordoma patients. The Scientific Advisory Board (SAB) includes leaders in chordoma research as well as other scientists with deep expertise in relevant areas such as cancer genomics and drug discovery. The Community Advisory Board (CAB) is composed of patients, caregivers, and family members across the world who represent the needs and perspectives of the chordoma community.
Funding for the Foundation’s work comes primarily from individuals within the chordoma patient community and those who care for them, with additional support from philanthropists and foundations that see the Foundation’s work as a model for what can be done to strategically address the challenges posed by a rare cancer. Other sources of funding for specific projects include governments and pharmaceutical companies.
Goals
CF relentlessly pursues three core goals to improve the lives of those affected by chordoma: better treatments, better medical care, and better patient experience .
Better Treatments
Existing treatment options for chordoma are inadequate and better treatments are urgently needed—treatments that enable patients to survive longer with better quality of life. Though advances in surgery and radiotherapy enable some patients to be cured, even with state-of-the-art care, more than half of chordoma patients ultimately experience disease progression. In addition to providing insufficient disease control, currently available treatments too often leave patients with deficits or complications that can significantly reduce quality of life. Moreover, when patients relapse after primary treatment, long-term survival is low and disease control is rarely, if ever, achieved. Unfortunately, therapies that can cure or effectively control metastatic or locally advanced disease do not yet exist. As a result, the median duration of overall survival in the Unites States remains 7.7 years, a figure CF is determined to change.
To improve these odds, CF seeks to catalyze the discovery and development of new treatments that benefit chordoma patients at every stage of the disease and will, ultimately, enable all patients to be cured. That means finding treatments that reduce morbidity and the risk of progression in the primary setting, as well as treatments that can effectively control advanced or metastatic disease. It also includes treatments that are effective for patients with tumors of every anatomical location: skull base, mobile spine, and sacrum.
Better Medical Care
CF believes that lives can be saved and outcomes can be improved by optimizing the care provided to chordoma patients. With state-of-the-art care, in certain circumstances, high rates of disease control and overall survival can be achieved. Conversely, when optimal care is not provided, outcomes can be far worse. Anecdotally, patients who contact CF and participants of a Facebook group for chordoma survivors commonly report that they have received inappropriate care. Moreover, many physicians at high-volume referral centers describe seeing patients after their care was previously mismanaged. Though the actual frequency of suboptimal care for chordoma patients is not known, results of a 2014 community-needs assessments survey completed by over 700 patients and caregivers hint at the magnitude of the problem: 24% report misdiagnosis, 38% report delayed diagnosis, and 18% report receiving inappropriate care.
CF aims to help improve the level of care provided to chordoma patients to give them the best possible chance of a good outcome. Specifically, the Foundation’s goals are to ensure that more patients receive:
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Timely and accurate diagnosis
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Referral to an experienced medical team
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Evidence-based treatment
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Access to experimental therapies, when appropriate
Better Patient Experience
CF is committed to making the experience of confronting chordoma easier and less detrimental for patients and those who care for them. As evidenced by results of the abovementioned needs assessment, the chordoma patient community faces a multitude of medical, emotional, and practical challenges ( Table 41.1 ). Notably, caregivers tend to bear these challenges to an even greater degree than the patients do. To reduce this burden, CF aims to help both patients and caregivers overcome and, ideally, avoid whatever challenges they may face throughout their journey with chordoma. Importantly, CF also strives to give those affected by chordoma opportunities to be a part of the solution by participating in research, volunteering, contributing philanthropically, and/or providing support to peers.
| Challenge | Patients (%) | Caregivers (%) |
|---|---|---|
| Reduced ability to work | 34 | 32 |
| Loneliness or isolation | 30 | 45 |
| Confusion or unanswered questions | 29 | 46 |
| Difficulty finding experienced physicians | 27 | 44 |
| Difficulty coping | 26 | 46 |
| Difficulty dealing with medical staff | 21 | 26 |
| Loss of employment | 21 | 10 |
| Difficulty talking about the experience | 18 | 23 |
| Financial distress | 17 | 21 |
| Difficulty helping family members cope | 13 | 34 |
Programs and Services
The Chordoma Foundation’s work is organized into three programmatic areas that advance each of its core goals:
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Research to advance the search for better treatments for chordoma
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Healthcare Improvement to promote better care for chordoma patients
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Patient Services to create a better experience for those affected by chordoma
All are essential and interlocking pieces of the Foundation’s overall mission, with progress in each area informing and enabling progress in the others. Programs and services in each area are described below.
Research
CF accelerates the search for better treatments by catalyzing research across every stage of the treatment-development process, from basic science through clinical research. The Foundation does this through three complementary approaches:
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Uniting and strengthening the research community
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Investing proactively in high-impact research
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Sharing data and biological resources
All of the Foundation’s research efforts are guided by a comprehensive Research Roadmap that defines specific research objectives and strategies to achieve them. The overall strategy embodied in this roadmap is to help identify and advance a pipeline of promising treatment approaches, ultimately culminating in the discovery of treatments demonstrated to be safe and effective for chordoma patients. It is based on the premise that multiple new treatments will likely be required to fully address the clinical need of chordoma patients, and that these treatments could take many forms, such as enhanced surgical techniques, radiotherapy, immune therapy, targeted therapy, or combinations thereof. Moreover, it anticipates that better treatments may be found by repurposing existing therapies, or may require shepherding the development of new therapies, depending on what is learned about the biology of the disease.
The roadmap encompasses five stages of research, each a critical part of the treatment-development process. Research in each stage is necessary, but not sufficient. To succeed in finding better treatments, and, ultimately, a cure, progress at all stages is needed ( Fig. 41.1 )
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Resource Development : Create the biological materials, disease models, and tools needed to enable important experiments.
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Target Discovery : Generate knowledge about the characteristics and vulnerabilities of chordoma that could be exploited as targets for treatment.
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Therapeutic Discovery : Discover new therapies against important targets in chordoma.
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Preclinical Research : Test promising therapies in biologically relevant disease models.
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Clinical Research : Study the safety, efficacy, and comparative effectiveness of promising treatments in chordoma patients.
The Research Roadmap was crafted and is regularly updated based on guidance from the Foundation’s SAB and MAB, and input from other chordoma researchers and subject matter experts. As knowledge about chordoma accumulates and new technologies emerge, priorities are updated to address new needs and opportunities.
Uniting and Strengthening the Research Community
The task of developing better treatments for chordoma requires the contributions of investigators possessing a wide range of knowledge and capabilities corresponding to the entire treatment-development continuum. Moreover, many important advances in chordoma research will only be possible through collaboration among investigators with complementary ideas or resources. Thus, CF aims to create a chordoma research community that includes the full complement of necessary expertise, and to facilitate coordination and collaboration among its members.
When CF started in 2007, the field of chordoma research was in its infancy. Few investigators were actively studying chordoma, and those who were worked in isolation. The Foundation’s first priorities were to bring together investigators interested in chordoma, and to recruit additional experts into the nascent field. To that end, in 2007, the Foundation partnered with the National Institutes of Health (NIH) to organize the First International Chordoma Research Workshop, held in Bethesda, MD. It was attended by over 50 scientists and clinicians—roughly half of whom had not previously studied chordoma, but possessed relevant expertise or interests. This marked the first time researchers interested in chordoma had ever gathered in one place, and, for nearly everyone in attendance, provided their first opportunity to interact with others studying chordoma. This first workshop had three main outcomes. First, it identified key unanswered questions and a set of research priorities around which the field could organize. These priorities formed the basis for the first iteration of the Foundation’s Research Roadmap. Second, it stimulated new ideas and inspired participants to launch a wave of new research projects. Third, it started relationships among participants, many of whom went on to collaborate in various ways. Since then, the Foundation has continued working to connect the global research community through a series of progressively larger International Chordoma Research Workshops, as well as various topic-specific meetings in the United States and Europe. In total, more than 300 investigators have attended CF research meetings.
Over time, CF has continually worked to generate more interest in chordoma and attract new researchers to the field. This has involved networking with investigators at leading academic medical centers, research institutes, and pharmaceutical companies, and exploring specific ways in which their expertise and interests are aligned with opportunities in chordoma research. For example, since the transcription factor brachyury was identified as a key driver and potential therapeutic target of chordoma, CF has worked to attract the interest of scientists who focus on developing drugs against transcription factors—a traditionally difficult class of drug targets. CF has also taken steps to lower barriers for investigators to enter the field by generating, organizing, and sharing biological materials and data commonly needed to embark on chordoma research (described below in greater detail).
Through these efforts, CF has become a central node in the chordoma research network, a position that enables it to facilitate information flow and collaboration among researchers within disconnected islands in the network who would not otherwise interact (e.g., developmental biologists and pathologists). Moreover, by staying in touch with researchers in this network, CF is able to maintain a bird’s eye view of much of the progress happening in the field. As a result, when researchers come to CF with questions, ideas, or challenges, CF is often able to connect them with others in the community who are in a position to help.
The effects of these efforts to strengthen the research community are quantifiable. The Foundation’s database has grown to include over 400 investigators involved in chordoma research. Additionally, surveys of participants who attended International Chordoma Research Workshops indicate that the field is becoming more interconnected. For example, in the year after attending the 2011 research workshop, participants reported a total of 174 new relationships and 30 new collaborations. Additionally, network density (proportion of all possible relationships actually established) increased and average path length (the number of steps between any two individuals in the network) decreased ( Table 41.2 ). These findings are important because each instance of collaboration represents work that might otherwise not have been possible, and each relationship represents the potential for future collaborations. Additionally, studies of scientific networks have demonstrated that higher network density and lower characteristic path length are associated with increased innovation within the network.
| Statistic | 2011 | 2012 | Change (%) |
|---|---|---|---|
| Number of relationships | 268 | 442 | +65 |
| Number of collaborations | 158 | 188 | +19 |
| Network density | 0.081 | 0.127 | +57 |
| Average path length | 2.7 | 2.2 | −23 |
The increase in the size and interconnectedness of the chordoma research community has coincided with a significant increase in research activity and new knowledge about the disease. As the field continues to grow, serving as a central node in the chordoma research network will become an increasingly significant function for the Foundation. Additionally, as the edges of knowledge about chordoma continue to expand into new areas and new technologies are developed, CF must continually work to bring investigators with relevant expertise and capabilities into the field. To facilitate this continued development of the community, the Foundation envisions an online research forum for chordoma modeled after Alzforum ( www.alzforum.org ) to enable more frequent interaction among chordoma researchers, and to provide an easy entry point for investigators new to the field.
Investing in High-Impact Research
Rather than simply reacting to requests for funding, as is typical among many disease research foundations, CF proactively initiates and supports research aligned with the objectives defined in its Research Roadmap. Recognizing that achieving many of those objectives will require resources on a scale beyond its means, CF invests strategically with a focus on programs and projects that can leverage or unlock resources or capabilities from other actors. Specifically, CF prioritizes research that enables and encourages researchers or companies to bring their resources to bear on chordoma and/or include chordoma in their ongoing research efforts.
CF invests in research through multiple programs and funding mechanisms, each designed to match specific needs and constraints of different types of research. This includes grants to support both investigator-initiated proposals as well as invited proposals focused on achieving specific research objectives. It also includes prizes, contract research, and strategic partnerships, as the circumstances dictate. Since 2007, the Foundation has invested over $5 million in research, including grants and prizes to over 30 investigators. Below is an overview of the programs and support mechanisms by which the Foundation advances research at each stage of the treatment-development process, as well as notable outcomes from each.
Resource Development
CF supports development of biological resources to meet the needs of the chordoma research community and to enable research identified in subsequent stages of the Research Roadmap. These include biospecimens, disease models (e.g., cell lines and mouse models), and other tools and reagents, as needed.
Biospecimens
A centerpiece of the Foundation’s research strategy is the CF Biobank , launched in 2012 with the goal of creating a source of high-quality, well-annotated biospecimens accessible to the chordoma research community. Operated under an institutional review board approved protocol, the CF Biobank collects and centrally stores chordoma tumor tissue, blood, and associated clinical data. The Biobank can collect samples from any hospital in the United States, providing patients an opportunity to donate their samples to help advance chordoma research. Once a patient consents to participate in the Biobank, CF staff works with the patient’s medical team and relevant hospital staff to facilitate collection of any excess tissue removed during an upcoming surgery and/or available archival samples not needed for clinical care. Patients can also elect to be contacted about follow-up requests for clinical data and/or other samples in the future. Additionally, several hospitals have partnered with CF to build this centralized biospecimen resource by contributing deidentified samples collected from chordoma patients under their own internal biobanking protocols. Whenever possible, tissue is collected in multiple formats: live, flash-frozen, and formalin-fixed. Samples undergo quality control analyses to confirm the diagnosis of chordoma and assess sample quality (e.g., percent necrosis and tumor cellularity). Within the first 5 years, the Biobank collected samples from more than 200 unique surgical cases.
Disease Models
One of the primary barriers to research progress when CF started was a lack of well-characterized disease models. Models identified as critical by the Foundation’s SAB and research workshop participants include cell lines, patient-derived xenograft (PDX) models, and genetically engineered mouse (GEM) models. To address this need, CF set a goal of developing the first GEM model and panels of multiple cell lines and PDX models representing the diverse clinical manifestations of the disease (e.g., different tumor locations, patient demographics, and treatment history).
As an initial step, CF provided research grants focused on characterizing existing cell lines and xenograft models, which were later described in several publications. Notably, Brüderlein et al. found that four of five putative chordoma cell lines (CCL3, CCL4, GB60, and CM319) were not in fact derived from chordoma cells. This revelation highlighted the need for independent validation of all disease models used by the chordoma research community. In response, the Foundation’s SAB developed a set of validation criteria for tumor-derived models based on morphology, biomarker expression, and genetics. Working through a contract lab, CF then established a validation pipeline to evaluate new cell lines and xenograft models against those criteria.
At the same time, CF also funded several investigators to attempt to develop new cell lines and PDX models, none of which were ultimately successful. Observing low success rates by its grantees and others attempting to develop new models, CF sought an approach that would encourage more attempts and alternative techniques. Inspired by Prize4Life—an organization offering prizes to incentivize specific ALS research outcomes—in 2010, CF began offering monetary prizes for the development of new chordoma cell lines, with the goal of eventually acquiring 10 new lines. To qualify for the prize, a cell line must meet the Foundation’s validation criteria and be contributed to a public repository. A prize had never previously been used to spur development of cancer cell lines, so the success of this approach was initially not certain. However, over time, it had the desired effect of encouraging numerous investigators to try their hand at developing new chordoma cell lines. Between 2010 and 2016, a total of 27 cell lines were submitted, of which 15 were validated. Having exceeded the initial goal of 10 cell lines, the Foundation continues offering prizes to incentivize development of additional lines representing more clinical subtypes. Once cell lines are validated, extensive genomic characterization is performed, including whole genome sequencing and RNA-seq.
Inspired by the success of the cell line prize, in 2013 CF began offering prizes for new PDX models. By 2015, three PDX models had been submitted, two of which were validated. However, recognizing that relatively few investigators had the necessary resources or facilities to attempt to establish PDX models, in 2015, CF launched its own centralized PDX development pipeline to attempt to increase the throughput of PDX model development. Live tissue collected through the Foundation’s biobanking protocol is shipped overnight to a contract lab where it is implanted in immune-compromised mice. Resulting models are validated, expanded, and, eventually, banked for future use and distribution. Through this same pipeline, CF also attempts to develop cell line–based xenograft models from all available cell lines. More recently, in 2015 CF funded the development of the first immune-competent xenograft model in humanized NOD scid gamma mice.
Since its inception, CF has provided grant support for several attempts to develop chordoma GEM models. These efforts have been spurred by the recent discovery of recurrent germline and somatic genetic alterations associated with chordoma. They are also aided by the recent development of mice engineered to express Cre recombinase with specificity for cells of notochordal lineage. In 2014, CF began a partnership with The Jackson Laboratory (“JAX”) to systematically attempt to develop a chordoma GEM model by performing a series of crosses between mouse strains engineered to recapitulate various genetic alterations found in human chordomas. Any resulting strains that are developed will be made available through the JAX mouse model repository.
Tools and Reagents
CF supports the development and characterization of various biological tools important for chordoma research. These may include, for example, assays, antibodies, and purified proteins. To the extent possible, CF seeks to develop these materials under arrangements that enable their free and unfettered use by academic investigators and minimize barriers to their use by companies.
Target Discovery
To identify new potential therapeutic approaches for chordoma, CF invests in a breadth of research to characterize the biology of the disease and uncover distinguishing features that could serve as targets for therapy. This includes, for example, research to identify aberrant cell-signaling pathways, genetic or epigenetic alterations, tumor-specific antigens, or relevant tumor–host interactions. The intent of these studies is to provide evidence indicating whether any existing therapies could hold promise for chordoma, or whether there are important targets against which new therapies should be developed.
CF has supported discovery research primarily through grants to academic investigators. Funded projects have involved a variety of unbiased, hypothesis-generating approaches including genomic, epigenomic, and proteomic analysis; super enhancer analysis; CRISPR and shRNA mediated loss of function screens; and small molecule screens. Target discovery grants have also supported more focused, hypothesis-driven approaches to elucidate specific aspects of chordoma biology. Among the most significant projects CF has supported is the “Chordoma Genome Project”—a collaborative effort involving investigators at the Wellcome Trust Sanger Institute, the Royal National Orthopedic Hospital and the University College London intended to catalogue all genomic alterations present in chordoma. Exome, transcriptome, and whole genome-sequencing data resulting from this project are available through the European Genome-phenome Archive ( https://www.ebi.ac.uk/ega/search/site/chordoma ). Most notably, it revealed that nearly all chordoma patients harbor a germline single nucleotide polymorphism in the T (brachyury) gene, providing strong evidence that brachyury contributes significantly to the pathogenesis of chordoma.
In the future, CF envisions creating a molecular analysis core service that would offer to the chordoma research community a fast and efficient way perform certain common experiments (e.g., immunohistochemistry, candidate gene sequencing, ChIP-seq) using the disease models and biospecimens acquired by the Foundation. Performing these experiments at large scale will reduce the time and cost of generating data, thus lowering the barrier for investigators to test hypotheses about potential targets of interest.
Therapeutic Discovery
Given the substantial time and expense involved in developing new cancer therapies, CF has focused its research investments on determining whether any existing therapies—that are already approved or in clinical development—could be beneficial for chordoma patients. In parallel, CF has also anticipated the possible need to create new therapies capable of exploiting key vulnerabilities or defining characteristics of chordoma that cannot be targeted with existing therapies. As research has advanced in recent years, it has become clear that chordoma harbors a number of molecular and genetic features common to other cancers, some of which could render chordoma susceptible to existing therapies. For example, multiple oncogenic kinases are frequently activated in chordoma, and tumor suppressors PTEN and p16 are often lost. Consequently, repurposing drugs that target corresponding signaling pathways may provide a promising near-term opportunity to identify better treatment options.
In the long run, however, a novel drug target may represent a stronger therapeutic opportunity. Currently, one such candidate target is the T (brachyury) gene, which appears to play the most central role in chordoma pathogenesis and cellular identity. The case for exploiting brachyury’s role in chordoma is now substantial. In brief, germline alterations in brachyury underlie both sporadic and familial chordoma, the T-gene locus is amplified in some chordomas, the brachyury protein is highly expressed in nearly all chordomas, and its presence appears to be critical for chordoma cell viability. Furthermore, brachyury is a tumor-specific antigen not detectable in normal tissues, except in the testes to a small degree.
Compelled by this body of evidence, CF has adopted as a research priority the discovery of new therapies that target brachyury, either directly or indirectly (e.g., through disrupting a critical interaction or another node in the brachyury signaling network). Thus, CF intends to initiate and support a portfolio of early drug discovery research focused on brachyury. However, the scale of investment likely required to create a new therapeutic entity also necessitates attracting outside resources. This may be aided by mounting evidence that brachyury plays an important role in the epithelial–mesenchymal transition and mediates metastasis in a variety of common carcinomas. Given that the potential market for therapies targeting brachyury may be far larger than just chordoma, CF sees opportunity in pursuing strategies to encourage and enable companies to focus resources on this new target. Already, two companies—GlobeImmune and Bavarian Nordic—have initiated efforts to develop therapies targeting brachyury, and CF hopes to inspire more companies to follow suit.
Preclinical Research
Preclinical research serves two important roles in the Foundation’s research strategy. First, it offers an efficient empirical approach to identify existing therapeutic entities that could be relevant to chordoma. Second, it provides a means of vetting the proposed therapeutic concepts and prioritizing which to take forward to clinical trials.
To determine whether any approved or experimental drugs could have activity in chordoma, CF has initiated and supported projects to test the activity of various drug libraries in chordoma cell lines. Among its first research priorities, CF partnered with the NIH Chemical Genomics Center (NCGC) to screen the NCGC Pharmaceutical Collection containing approximately 2800 clinically approved and investigational drugs—including nearly all drugs approved by the FDA and EMA. Importantly, this screening experiment revealed over 20 drugs that inhibited chordoma cell growth at therapeutically relevant concentrations. Additionally, CF has worked to include chordoma cell lines in several ongoing large-scale drug screening projects in industry and academia, interrogating the effect of thousands more compounds.
To test hypotheses about candidate therapies, CF has provided several grants to support in vitro and in vivo proof of concept experiments. Notably, when Siu et al. at Johns Hopkins University developed the first PDX model of chordoma in 2012, CF funded this group to test drugs identified through the NCGC screen in their model. Their experiments demonstrated that the EGFR inhibitor erlotinib significantly reduced tumor growth—the first agent found to have activity in a patient-derived chordoma xenograft (PDX) model. At the same time, as the field became more active and more therapeutic targets were described, CF recognized a need to enable more investigators to evaluate the activity of their own candidate therapies in preclinical models. However, due to the slow growth of chordoma cell lines and PDX models, these experiments are time-consuming, costly, and labor-intensive, putting them out of reach for many investigators. For example, acquiring and expanding a cohort of chordoma-bearing mice for in vivo experiments takes upward of a year. These barriers made generating preclinical proof of concept data a key gating factor that kept a growing number of promising therapeutic concepts from progressing to clinical trials.
To help bridge this gap, in 2015, CF launched a centralized Drug Screening Pipeline that conducts in vitro and in vivo efficacy studies in a panel of well-characterized preclinical models acquired by the Foundation. Experiments are performed by a contract lab, offering investigators and companies the ability to test therapies of interest quickly, with no upfront investment in personnel or experimental set-up, and without encumbrance of their intellectual property. By continually maintaining cohorts of tumor-bearing animals, experiments can be carried out multiple times per year, and, by performing experiments at scale, the unit cost of evaluating each therapy decreases significantly. This service is offered to the research community on a cost-recovery basis, and, when resources permit, is subsidized by the Foundation. It also gives CF the ability to efficiently test promising therapeutic concepts identified by its staff or SAB. Because the throughput of in vivo experiments is finite—constrained by the slow growth rate of chordoma xenograft models—and the cost is not insignificant, CF carefully prioritizes agents to test, maintaining a queue including both internally and externally nominated agents. Going forward, the goal is to evaluate existing therapies corresponding to every target identified proposed in the literature and to quickly evaluate relevant new therapies as new hypotheses emerge.
Clinical Research
The Foundation’s investment in clinical research is oriented around two goals. First, CF aims to facilitate clinical trials to evaluate well-justified therapeutic approaches. Second, CF aims to maximize learning from the real-world clinical care of chordoma patients.
Clinical Trials
When CF started in 2007, only one clinical trial of a systemic therapy had been completed, a 15-patient phase I trial of the cytotoxic agent rubitecan. In the following 7 years, as knowledge about activated signaling pathways in chordoma emerged, four phase II trials of various kinase inhibitors were conducted, enrolling a total of 104 patients. Each showed modest antitumor activity, inducing short-term disease stabilization or small dimensional responses in some patients, but no long-term stabilization or objective responses as measured by RECIST criteria. Additionally, in 2013, CF worked with investigators at the NCI to include chordoma patients in an ongoing phase I study of a therapeutic vaccine targeting brachyury. By 2014, molecular, preclinical, and anecdotal clinical evidence about a number of additional therapeutic approaches was mounting, but CF observed that trials were not moving ahead due to several obstacles: lack of accepted clinical endpoints, lack of funding, and/or the perception that patient recruitment would be too difficult.
To help address the first obstacle, CF convened a roundtable discussion in 2014 with representatives from the U.S. Food and Drug Administration, industry, and leading clinicians to discuss appropriate clinical-trial endpoints. A similar meeting was held in 2015 organized by the European Medicines Agency and Rare Cancers Europe. These discussions made clear that regulatory bodies would consider approving drugs for chordoma based on single arm studies; however, only with objective response endpoints. For a drug that induces disease stabilization to be approved, it must show superiority to a control group or well-documented natural history. While clarifying a potential path to approval for some drugs, clinicians unanimously agreed that objective response was an insufficient benchmark of clinical benefit for chordoma patients and that prolonged progression-free survival or symptomatic improvement would be desirable outcomes as well. These discussions made clear the importance of better characterization of the natural history of chordoma and of new clinical-trial endpoints incorporating quality of life measures. These are both priorities that the Foundation has embraced in its Research Roadmap.
To address the latter two obstacles, CF worked with its MAB to develop a policy and a formal process for funding clinical trials and facilitating patient participation. When needed, CF will provide grant funding to support nondrug trial costs and correlative studies associated with investigator-initiated proof of concept trials. Additionally, the Foundation will leverage its extensive network of treating physicians and connections within the chordoma patient community to generate awareness and provide education about clinical trials open to chordoma patients. The Foundation’s support of clinical trials is conditioned upon a multistep review process evaluating both scientific rationale and clinical relevance. In brief, clinical-trial concepts are first jointly reviewed by the Foundation’s SAB and MAB. To qualify for support, a therapy must have strong mechanistic rationale, evidence of activity in at least two preclinical models, and/or at least two documented cases of clinical activity. The therapy must also meet an important clinical need and be appropriate for the chordoma patient population. Once a trial concept is endorsed, investigators are invited to submit a full trial protocol, which is then reviewed by the Foundation’s MAB to evaluate feasibility and safety before receiving approval from the Foundation. During the Foundation’s first two concept review cycles, 24 trial concepts were submitted, of which 6 were endorsed. The Foundation’s goal is to support a pipeline of at least 10 clinical trials by 2020.
Observational Research
CF seeks to more rigorously characterize the natural history of the disease, to identify correlates of outcome that could help inform improvements to clinical practice, and to identify patterns of response to therapies used off-label that could provide rationale for a formal clinical trial. To achieve these goals, CF envisions supporting one or more longitudinal registries that would systematically collect both clinical data and patient-reported outcomes over time. To this end, CF has provided modest pilot funding for a multi institutional European registry spearheaded by the University of Leiden. Additional registry plans are under consideration.
Sharing Data and Biological Resources
Like any scientific endeavor, finding better treatments for chordoma is an iterative process of incremental knowledge accumulation. Discoveries build upon prior discoveries. Results of experiments inspire subsequent experiments. Data generated at each stage in the treatment-development process stimulates and informs research at the next stage. In other words, information about chordoma is a crucial enabler of research progress. In combination with information, biological resources such as biospecimens and disease models are also critical inputs needed to enable most preclinical cancer research. CF believes that chordoma research can advance most quickly when these crucial inputs are readily accessible. As such, CF seeks to make data generated about chordoma and relevant biological resources broadly available to the research community with minimal delay.
Data
Several CF programs and policies serve to promote access to information about chordoma. First, the Foundation’s research workshops provide a forum for investigators to exchange new, unpublished findings, enabling participants to learn about and build upon the work of others sooner. For example, at the first research workshop in 2007, Dr. Vijaya Ramesh from Massachusetts General Hospital presented unpublished data showing that the mTOR pathway is activated in the vast majority of chordomas. This finding was subsequently confirmed by Dr. Silvia Stacchiotti and colleagues at the Istituto Nazionale dei Tumori in Milan, providing rationale to treat a series of advanced chordoma patients with the mTOR inhibitor sirolimus. Ramesh et al. published their results in early 2009. By then, Stacchiotti et al. had already treated a series of 10 chordoma patients with sirolimus, observing clinical benefit in 8 out of 9 evaluable patients.
In between its periodic research workshops, with permission, CF routinely makes personal introductions between researchers with new findings and others who are in a position to build upon their results. What’s more, CF research grants are awarded with a requirement that grantees agree to publish and/or deposit data generated with CF funding into a public data repository within a predefined timeframe. Similarly, data generated by CF through contract research that its sponsors are made publicly available to the extent this does not conflict with the Foundation’s obligations to its collaborators. For example, CF provides access to genomic data generated from its collections of cell lines and PDX models through a cloud-based data repository.
In addition to facilitating sharing of unpublished data, CF also seeks to make the entire published body of knowledge about chordoma easily accessible to the research community. As a first step toward that goal, CF has built and maintains an online “Target Dashboard” containing an up-to-date summary of all published data regarding potential therapeutic targets for chordoma ( www.chordoma.org/targets/ ). This provides researchers with an easy way to find out what is known about a particular target in chordoma, and gives companies an indication of whether assets in their portfolios could be applicable to chordoma.
Biological Resources
Traditionally, finding and accessing biospecimens, disease models, and other biological materials is often a time-consuming and difficult process. It may also beonerous for the creators of such resources to furnish them to others. Furthermore, relying on peer-to-peer sharing of biological resources can result in poor quality control—as demonstrated above by sharing of misidentified chordoma cell lines—contributing to widespread irreproducibility in preclinical cancer research.
To overcome these challenges and ensure that researchers have unfettered access to the biological resources they need, CF has established centralized repositories of biospecimens and disease models. As mentioned above, the CF Biobank provides a source of tumor tissue as well as matched blood and clinical data. Additionally, since 2008, CF has provided a collection of validated chordoma cell lines to the research community. Originally, cell lines were distributed through a partnership with the lab of Dr. Michael Kelley at Duke University. To facilitate even greater ease of access worldwide, in 2014, the collection was moved to the American Type Culture Collection (ATCC) in Manassas, VA—the world’s largest cell line distributor. When necessary, CF also independently distributes cell lines to researchers through a contract laboratory prior to their availability at ATCC (the deposit agreement and accessioning process typically take over a year). Between 2008 and 2015 cell lines were distributed by ATCC and CF to a total of 101 labs and companies across the world, enabling numerous research projects that otherwise would not have been possible. In a similar fashion, in 2015, CF also established a repository of PDX models through a contract laboratory. Going forward, CF will continue working to ensure that any biological resource needed to achieve objectives in the Research Roadmap are available to the research community.
Healthcare Improvement
In addition to pushing the envelope of treatment options for chordoma, CF is committed to working with healthcare providers to improve the quality of care delivered to chordoma patients with currently available treatment modalities. At present, the Foundation’s strategy for healthcare improvement focuses on two priorities:
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Standardization : Generate consensus and create evidence-based guidelines regarding best practices for the clinical management of chordoma.
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Education : Disseminate information and best practices to healthcare providers involved in caring for chordoma patients.
These priorities will likely evolve over time as the Foundation’s capabilities continue to grow and new treatments become available.
Standardization
A condition precedent to improving care for chordoma patients is defining what constitutes optimal care. When CF started, there were no published treatment guidelines and disagreement existed among experts about how best to manage chordoma. In 2013, the National Comprehensive Cancer Network (NCCN) published the first guidelines for managing chordoma as part of the second version of the NCCN Clinical Practice Guidelines in Oncology: Bone Cancer . A significant step toward standardizing care, these guidelines provide evidence-based recommendations and guiding principles regarding the types of treatment appropriate for chordoma patients according to tumor location and disease status. However, technical details regarding how those treatments ought to be performed or delivered are beyond the scope of the NCCN guidelines. Because procedural nuances— radiation dose distribution, biopsy technique, and surgical approach—can significantly impact treatment outcomes and patient quality of life, CF sought to facilitate development of even more in-depth and actionable guidelines. To that end, CF worked with the European Society of Medical Oncology and the Istituto Nazionale dei Tumori (INT) in Milan to convene a multidisciplinary group of over 40 specialists and patient advocates from the United States and Europe to develop consensus about best practices for the diagnosis and treatment of chordoma. This initial consensus group meeting focused on the management of localized, primary chordoma tumors, leaving the management of recurrent or metastatic disease for a subsequent meeting. In 2015, the group’s recommendations were published as a consensus statement in The Lancet Oncology in an attempt to reach the broadest audience of doctors likely to encounter chordoma patients. Then, later in 2015, CF and INT convened a second consensus group meeting focusing on the management of recurrent and advanced chordoma in which over 60 specialists participated and 15 groups presented unpublished case series. A second consensus paper focusing on recurrent disease was published in 2017 in Annals of Oncology. Going forward, CF plans to continue convening periodic consensus group meetings to update and further refine best practice recommendations as new treatment options and new knowledge emerge.
Education
Key to improving care for chordoma patients is for healthcare providers to know how to appropriately diagnose and manage this disease. Though an important part of the Foundation’s long-term plan to improve patient care, thus far, the Foundation’s investments in education for medical professionals has been modest. Principally, the Foundation’s website offers a section with educational content geared toward medical professionals unfamiliar with chordoma, including links to authoritative references such as this book and the abovementioned treatment guidelines. Additionally, the Foundation’s Target Dashboard helps oncologists become educated about potential therapeutic targets in chordoma so that they can make more well-informed choices when prescribing systemic therapies off-label or referring their patients to clinical trials. The Foundation’s international research workshops and two physicians’ conferences in Europe have also provided an opportunity for clinicians to learn about and discuss state-of-the-art care for chordoma.
Going forward, as physicians increasingly turn to online sources for education, CF plans to support efforts to ensure that the most popular online medical references —including UpToDate, Medscape, Wikipedia, and Epocrates—contain information reflecting the current state of the art for chordoma care. In the future, CF also envisions sponsoring CME and other educational campaigns geared toward physicians most likely to first encounter and diagnose chordoma patients prior to referral to a specialist—including radiologists, neurologists, and internists.
Patient Services
From its start, CF has served as a resource to patients and families in need of information and support. As the Foundation has grown, the scope of its services for the patient community has expanded. Beginning in 2015, CF launched a suite of services intended to address the most significant challenges, needs, and desires of the chordoma patient community. Currently, the Foundation’s strategy for patient services focuses on three priorities:
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Education : Provide reliable and actionable information about chordoma, treatment options, and what to expect as a patient
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Navigation : Help patients overcome barriers to getting the treatment and supportive care they need
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Support : Provide opportunities to develop supportive relationships with peers in the chordoma community
Education
A deeply held belief at CF is that every patient ought to have access to the knowledge they need to make well-informed decisions about his or her healthcare. The Foundation sees as one of its reasons for being the translation of technical information and knowledge possessed by the medical profession into terms that are understandable and meaningful to the chordoma patient community. To that end, CF offers a variety of educational resources in multiple formats intended to help patients and caregivers find and make sense of information that is relevant to their lives. For example, the Foundation’s website ( www.chordoma.org ) contains a wealth of information about chordoma and treatment options, accessed by over 8,000 unique users each month. Moreover, news distributed through the Foundation’s blog, newsletter, and social media channels provides updates about new educational content as well as treatment and research advances. In 2015, CF produced the first in a planned series of educational materials, entitled Expert Recommendations for the Diagnosis and Treatment of Chordoma , based on the consensus guidelines published in The Lancet Oncology . This booklet is available in multiple languages on the Foundation’s website as well as in print. Additionally, CF has hosted a series of “Community Conferences” in the United States and Europe designed to educate patients and caregivers about the latest advances in chordoma treatment and research, as well as strategies for managing the effects of the disease. Most recently, CF developed an “Expert Answers Video Series” in which leading chordoma physicians provide answers in plain language to common treatment-related questions. The Expert Answers series as well as speaker presentations from past conferences and other educational videos are available on the Foundation’s YouTube channel ( www.youtube.com/ChordomaFoundation ).
In the future, CF aims to continue enhancing its educational resources by tailoring materials to the needs of different subgroups of the patient community, creating materials to address more common questions and sources of confusion, and translating materials into even more languages.
Navigation
One of the most important roles that CF plays is to help patients find and access appropriate care throughout every step of their journey with chordoma. The cornerstone of this effort is the Foundation’s Patient Navigation Service , which provides one-on-one assistance from a trained patient navigator. Patients and caregivers can contact the Patient Navigation Service with a wide range of questions, or simply to get help figuring out where to start. The role of this service is to identify and, to the extent possible, help patients overcome any barrier that stands in the way of getting high-quality care. The Patient Navigation Service does not provide medical advice. Rather, it guides patients to useful information, helps them understand important concepts, provides referrals to experienced healthcare providers, and assists them in addressing any obstacles or challenges they face. When appropriate, it offers information about clinical trials and other resources or services that may be helpful. In its first two years, more than 700 patients or family members from over 40 countries utilized this service.
The personalized assistance provided by the Patient Navigation Service is complemented by several online self-service resources, including:
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A Doctor Directory that provides a vetted list of specialists who have experience treating chordoma and meet criteria established by the Foundation’s Medical Advisory Board ( www.chordoma.org/doctor-directory ).
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A Clinical Trials List which includes all open clinical trials specifically recruiting chordoma patients as well as other relevant trials identified by the Foundation’s MAB ( www.chordoma.org/clinical-trials ).
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A Helpful Resources List which includes information about organizations, service providers, and vendors that can offer assistance to chordoma patients and caregivers ( www.chordoma.org/helpful-resources/ ).
Support
In addition to addressing practical needs, CF is also concerned with the emotional well-being of patients and those who care for them. Some of the main emotional challenges identified by the Foundation’s community-needs assessment include loneliness, isolation, and difficulty talking about the disease. The rarity of chordoma, coupled with the unusual and sometimes profound effects it has on patients’ lives, often makes it difficult for patients and caregivers to find anyone in their personal network who can truly empathize. Consequently, many find it beneficial and comforting to connect with others who have dealt with chordoma. To that end, CF provides ways for members of the chordoma community to connect with and support one another. The Foundation’s Peer Support Program matches individuals in need of emotional support with peer guides who have been through a similar experience. Guides receive training in evidence-based peer support best practices to ensure a high-quality experience for both parties. Additionally, CF Community Conferences and accompanying social events provide a unique opportunity to meet and form bonds with a network of peers. Going forward, CF plans to launch an online community that will enable greater connectivity and more frequent interaction among patients and caregivers around the world.
Related posts:
Pathology of Chordoma and Chondrosarcoma of the Axial Skeleton
Midline Subfrontal Approaches: The Transbasal Approach and Extended Modifications to Access the Clivus
Chordomas and Chondrosarcomas of the Skull Base: Transpetrosal Approaches
Surgical Management of Chordomas and Chondrosarcomas of the Cervical Spine
Anatomical Considerations for Resection of Chordomas and Chondrosarcoma of the Sacrum
Systemic Therapies for Locally Recurrent or Metastatic Disease
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