Following our research roadmap, grants have focused on the development and characterization of model systems needed to study chordoma biology, and test new treatments. Model systems are research tools that mimic the behavior of human tumors, and allow researchers to study cancer without experimenting on people. They are needed to develop virtually any type of new therapy, however limited availability of valid models of chordoma is a major barrier to progress. Because there is no guarantee of success in creating model systems, grants were awarded to several research groups who are employing different, complementary approaches in parallel.
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A Transgenic Mouse Model of Chordoma Brian Harfe, PhD
Department of Molecular Genetics and Microbiology
University of Florida $25,500 grant cofunded with the Liddy Shriver Sarcoma Initiative Dr. Harfe is a developmental biologist who studies the formation of the spine and intervertebral discs (IVD). In 2008 he conclusively demonstrated that the center of the IVD is derived from notochordal cells, and also discovered that single notochordal cells remain dispersed in the mouse vertebrae through adulthood. Dr. Harfe believes that these notochordal cells are lodged in the vertebrae give rise to chordomas, when a gene called Sonic Hedgehog – which is expressed in notochord but not in IVD - is inappropriately reactivated. He is therefore attempting to spur the development of chordomas in mice by activating Sonic Hedgehog in notochordal cells. | 
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Generation of a chordoma mouse model through conditional inactivation of PTEN or TSC1 in the mouse notochord Vijaya Ramesh, PhD
Center for Human Genetics
Massachusetts General Hospital $25,000 Model Systems Grant - Transgenic Animal Model Dr. Ramesh is a molecular-neurogeneticist who studies the function of tumor suppressor genes and genetic tumor syndromes such as Neurofibromatosis and Tuberous Sclerosis Complex (TSC). Dr. Ramesh first reported a possible connection between chordoma and TS in 2004. Since then she and others have discovered that the mTOR pathway, which is regulated by TSC genes, is activated in nearly all chordomas. Therefore Dr. Ramesh and Dr. Harfe are collaborating to develop a mouse model by knocking out two tumor suppressor genes that regulate the mTOR pathway, called PTEN and TSC1, in the mouse notochord. They hypothesize that knocking out these genes will cause the mice to develop chordomas. | 
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Generating Chordoma Cell Lines and Xenographs Adrienne Flanagan, MD, PhD
University College London Cancer Institute and The Royal National Orthopaedic Hospital, Stanmore $25,000 Model Systems Development Grant - Cell Lines & Xenographs Dr. Flanagan is a bone pathologist and runs a lab focused on identifying the molecular etiology of bone tumors. She published the first gene expression profile data for chordoma in 2006, and identified that brachyury was uniquely expressed in chordoma. Since then her lab has studied a variety of signaling pathways in chordoma and has performed mutational analysis in several dozen candidate genes. In this project she will establish new chordoma cell lines and xenographs using a variety of methods including telomerase immortalization, tumor cell enrichment, and organotypic culturing. | 
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Development and Characterization of Chordoma Xenographs David Loeb, MD, PhD
Department of Oncology
Johns Hopkins University $25,000 Model Systems Development Grant - Xenographs Dr. Loeb is a pediatric medical oncologist and co-director of the Johns Hopkins Sarcoma Center. In collaboration with Dr. Ziya Gokaslan and his colleagues in the Department of Neurosurgery, Dr. Loeb is collecting chordoma tissue from surgeries at Johns Hopkins, and implanting this tissue in immunodeficient mice in an attempt to establish a serially transplantable chordoma xenograph model. He is also characterizing the xenographs on a molecular level to ensure that they faithfully represent the tumors from which they were derived. | 
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Molecular Validation of Chordoma Mouse Xenographs Elena Tamborini, PhD
Department of Pathology
Istituto dei Tumori Milan $25,000 Model Systems Development Grant - Xenographs Dr. Tamborini is a molecular biologist in the lab of Dr. Silvana Pilotti, and is a colleague of Dr. Paolo Casali, who has one of the most active chordoma oncology practices in Europe. This group in Milan has previously implanted chordomas in mice, with limited success. In this project, Dr. Tamborini is performing detailed genetic and biochemical analysis of the implanted tumors and comparing them to the primary tumors from which they were derived. This validation is important because it will indicate whether these xenographs are suitable models of chordoma. | 
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Characterization of Chordoma Cell Lines and Tumors Michael Kelley, MD
Department of Medicine, Division of Hematology and Oncology
Duke University Medical Center $45,000 Research Grant The Chordoma Foundation is supporting a variety of research projects in Dr. Kelley’s lab by partially funding the salary of research scientist Dr. David Alcorta. This work includes performing genetic and genomic analysis of chordoma, investigating the role of a protein called brachyury in chordoma, studying the PI3K pathway in chordoma, and creating new chordoma cell lines. In addition, Dr. Alcorta is working with the NIH Chemical Genomics Center on a project to screen all FDA approved drugs against chordoma cell lines. He also manages the Chordoma Foundation Cell Line Panel, distributing chordoma cells to researchers across the world. | 
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