• By what mechanism (s) does duplication of the brachyury gene cause susceptibility to chordoma?
  • What genes does brachyury regulate?
  • What genes regulate brachyury?
  • What proteins does brachyury interact with?
• 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?

References