TY - JOUR
T1 - Chemotherapy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin
AU - D'Alessandris, Quintino Giorgio
AU - Cenci, Tonia
AU - Martini, Maria Cristina
AU - Bianchi, Federico
AU - Maira, Giulio
AU - Larocca, Luigi Maria
AU - Pallini, Roberto
AU - Ricci-Vitiani, Lucia
AU - Runci, Daniele
AU - Stancato, Louis
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Adult
KW - Antineoplastic Agents
KW - Cell Death
KW - Cell Line, Tumor
KW - Cell Survival
KW - Chordoma
KW - Drug Screening Assays, Antitumor
KW - Female
KW - Humans
KW - Magnetic Resonance Imaging
KW - Mutation
KW - Primary Cell Culture
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins B-raf
KW - Sirolimus
KW - Skull Base Neoplasms
KW - Treatment Outcome
KW - Tumor Burden
KW - Xenograft Model Antitumor Assays
KW - ras Proteins
KW - Adult
KW - Antineoplastic Agents
KW - Cell Death
KW - Cell Line, Tumor
KW - Cell Survival
KW - Chordoma
KW - Drug Screening Assays, Antitumor
KW - Female
KW - Humans
KW - Magnetic Resonance Imaging
KW - Mutation
KW - Primary Cell Culture
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins B-raf
KW - Sirolimus
KW - Skull Base Neoplasms
KW - Treatment Outcome
KW - Tumor Burden
KW - Xenograft Model Antitumor Assays
KW - ras Proteins
UR - http://hdl.handle.net/10807/54195
M3 - Article
VL - 15
SP - 773
EP - 782
JO - Neoplasia (New York, N.Y.)
JF - Neoplasia (New York, N.Y.)
ER -