Chemotherapy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin

Luigi Maria Larocca, Roberto Pallini, Tonia Cenci, Maria Cristina Martini, Federico Bianchi, Giulio Maira, Lucia Ricci-Vitiani, Daniele Runci, Louis Stancato

Risultato della ricerca: Contributo in rivistaArticolo in rivista

11 Citazioni (Scopus)

Abstract

Skull base chordomas are challenging tumors due to their deep surgical location and resistance to conventional radiotherapy. Chemotherapy plays a marginal role in the treatment of chordoma resulting from lack of preclinical models due to the difficulty in establishing tumor cell lines and valuable in vivo models. Here, we established a cell line from a recurrent clival chordoma. Cells were cultured for more than 30 passages and the expression of the chordoma cell marker brachyury was monitored using both immunohistochemistry and Western blot. Sensitivity of chordoma cells to the inhibition of specific signaling pathways was assessed through testing of a commercially available small molecule kinase inhibitor library. In vivo tumorigenicity was evaluated by grafting chordoma cells onto immunocompromised mice and established tumor xenografts were treated with rapamycin. Rapamycin was administered to the donor patient and its efficacy was assessed on follow-up neuroimaging. Chordoma cells maintained brachyury expression at late passages and generated xenografts closely mimicking the histology and phenotype of the parental tumor. Rapamycin was identified as an inhibitor of chordoma cell proliferation. Molecular analyses on tumor cells showed activation of the mammalian target of rapamycin signaling pathway and mutation of KRAS gene. Rapamycin was also effective in reducing the growth of chordoma xenografts. On the basis of these results, our patient received rapamycin therapy with about six-fold reduction of the tumor growth rate upon 10-month follow-up neuroimaging. This is the first case of chordoma in whom chemotherapy was tailored on the basis of the sensitivity of patient-derived tumor cells.
Lingua originaleEnglish
pagine (da-a)773-782
Numero di pagine10
RivistaNeoplasia (New York, N.Y.)
Volume15
Stato di pubblicazionePubblicato - 2013

Keywords

  • Adult
  • Antineoplastic Agents
  • Cell Death
  • Cell Line, Tumor
  • Cell Survival
  • Chordoma
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Mutation
  • Primary Cell Culture
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf
  • Sirolimus
  • Skull Base Neoplasms
  • Treatment Outcome
  • Tumor Burden
  • Xenograft Model Antitumor Assays
  • ras Proteins

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