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Chordoma: Questions and Hypotheses

  • By what mechanism (s) does duplication of the brachyury gene cause susceptibility to chordoma?
  • Is brachyury amplified in sporadic chordomas?
  • Are chordomas dependent on expression of brachyury?
  • Brachyury duplication was found in 4 of 7 families with familial chordoma [1] - what other genetic events increase susceptibility to chordoma?
  • What is responsible for frequent activation of the PI3K/akt/mTOR pathway in chordomas?
    • Can combined treatment with PI3K inhibitor and mTORC1 provide clinical benefits to chordoma patients? [2]
  • Are pediatric chordomas genetically/biologically distinct from adult-onset chordomas?
  • What explains the co-occurrence of chordoma and Tuberous Sclerosis?
    • Why have most cases of chordomas with TS been diagnosed in very young children?
    • Are all or most pediatric chordomas a manifestation of TS?
  • Are chordomas of different anatomic locations biologically different?
  • What accounts for low rate of distant metastasis?
  • Chordomas are thought to arise from notochordal cells lodged inside the vertebrae, which are derived from the same population of cells that forms the nucleus pulposus of the intervertebral disc. [3] Why, then, do chordomas arise from within the bone and not the intervertebral disc? Is there some factor in the bone that causes notochordal cells to proliferate?
  • Chordomas are comprised of multiple morphologically distinct cell types. [4] Are all these cell types neoplastic or is one cell type responsible for neoplasticity?
  • Why do chordomas characteristically form intralesional fibrous septae and lobules? [5]
  • Why do ferrets have a higher incidence of chordomas than other animals? [6] Is there something about the brachyury gene in ferrets that contributes to chordoma susceptibility?
  • Are chordomas generally hypoxic?
  • Why are chordomas highly radio-resistant?
  • Why are chordomas resistant to cytotoxic agents?
  • Do systemic drugs reach chordomas ?
  • Are there are any tumor-specific rearrangements in chordomas?
  • Are there any clear-cut diagnostic criteria for differentiating between chondroid chordomas and chondrosarcomas?
  • Is the loss of 3p an early event in chordoma genesis?
  • Are tumor suppressor genes or mismatch repair genes (located at 1p31 and 3p14) and oncogenes (located in 7q36) involved in chordoma genesis?
  • Is there a functional relationship in chordomas between galectin-3 and laminin, perhaps in modulation cell adhesion and motility?
  • Does E-cadherin play a role in chordoma tumor cell adhesion?
  • What is the significance of cell cycle aberrations in chordoma?
  • Given that EGFR is frequently expressed and phosphorylated in chordomas, could treatment with EGFR inhibitors effective?
  • Are EGFR/PDGFRB heterodimers responsible for imatinib resistance?
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  1. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Yang, X.R., Ng, D., Alcorta, D.A., Liebsch, N.J., Sheridan, E., Li, S., Goldstein, A.M., Parry, D.M., Kelley, M.J. Nat. Genet. (2009) [Pubmed]
  2. Aberrant hyperactivation of akt and Mammalian target of rapamycin complex 1 signaling in sporadic chordomas. Han, S., Polizzano, C., Nielsen, G.P., Hornicek, F.J., Rosenberg, A.E., Ramesh, V. Clin. Cancer. Res. (2009) [Pubmed]
  3. Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation. Choi, K.S., Cohn, M.J., Harfe, B.D. Dev. Dyn. (2008) [Pubmed]
  4. Tissue culture study of a sacrococcygeal chordoma with further ultrastructural study. Fu, Y.S., Pritchett, P.S. Acta. Neuropathol. (1975) [Pubmed]
  5. Intralesional fibrous septum in chordoma: a clinicopathologic and immunohistochemical study of 122 lesions. Naka, T., Boltze, C., Kuester, D., Samii, A., Herold, C., Ostertag, H., Iwamoto, Y., Oda, Y., Tsuneyoshi, M., Roessner, A. Am. J. Clin. Pathol. (2005) [Pubmed]
  6. A histomorphologic and immunohistochemical study of chordoma in twenty ferrets (Mustela putorius furo). Dunn, D.G., Harris, R.K., Meis, J.M., Sweet, D.E. Vet. Pathol. (1991) [Pubmed]
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