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.