Abstract
Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRβ inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC50s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322, and CF365 chordoma tumor models in vivo In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma. Mol Cancer Ther; 17(3); 603-13. ©2017 AACR.
Highlights
Chordomas are primary malignant bone tumors that arise along the axial skeleton, usually in the sacrum or skull-base, and with low frequency in the mobile spine
We assembled a panel of chordoma cell lines which included cells of sacral origin like the widely used U-CH1 [28] and U-CH2 [26], the recently established MUG-Chor1 [30] and JHC7 [8], and the first available clival cell line UM-Chor1 [31]
A few clinical trials have been conducted so far to assess the efficacy of targeted therapeutic agents in chordoma [20,21,22,23,24], certainly limited by the exiguous number of preclinical models of this indication available so far
Summary
Chordomas are primary malignant bone tumors that arise along the axial skeleton, usually in the sacrum or skull-base, and with low frequency in the mobile spine. With an incidence below 1:1,000,000, and account for 1% to 4% of all primary bone malignancies. They are typically late onset tumors with a peak incidence between the fifth and sixth decades of life, but can occur in children and young adults. Chordomas are slow growing tumors, but are characterized by a high recurrence rate even after complete surgical resection of the primary tumor. Distant metastases occur in 20% to 30% of cases [1], but local recurrences affect >50% of patients [2].
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