Targeting FGFR/MEK/ERK/Brachyury pathway to inhibit chordoma cell growth

Chordoma is a rare sarcoma believed to originate from malignant transformation of notochordal remnants and accounts for 2-4% of all primary bone malignancies. Previous studies have found that brachyury expression in chordoma is necessary to maintain cell growth. However, the mechanism of brachyury-promoted growth in chordoma is not clear. Brachyury is not expressed in normal adult tissues except for the testes, suggesting that this unique protein may represent a promising therapeutic target. An important transcription factor within the T-box family of genes, brachyury is expressed in normal, undifferentiated embryonic notochord in the axial skeleton and plays an evolutionarily conserved function in mesoderm development through fibroblastic growth factor (FGF) signaling. Our preliminary data suggests that chordoma cell lines (UCH1, UCH2 and JCH7) express FGF receptors (FGFR-2 and FGFR-3), mitogen-activated protein kinase kinase (MAPKK, MEK) and extracellular signal-regulated kinase (ERK). Inhibition of FGFR, MEK and ERK phosphorylation decreases brachyury expression and inhibits cell growth. These data indicate that the regulation of FGFR/MEK/ERK/Brachyury may be critical for chordoma growth and metastasis.

We propose targeting FGFR/MEK/ERK/Brachyury with small molecules dovitinib and GDC-0973 for the treatment of chordoma in vitro. The specific aims of this proposal are 1) to identify the regulatory role of FGFR/MEK/ERK/Brachyury through integrating the global gene expression profile and ChIP/ChIP-seq data. 2) To investigate the inhibitory effects of FGFR inhibition using dovitinib on chordoma pathophysiology in vitro and 3) To investigate the inhibitory effects of MEK/ERK inhibition using GDC-0973 on chordoma pathophysiology in vitro. The results from this study will 1) demonstrate the signaling network profile including FGFR pathway and crosstalk between FGFR/MEK/ERK and brachyury, 2) clarify the contribution of the FGFR/MEK/ERK/Brachyury pathway to chordoma cell growth, 3) define how targeting the FGFR/MEK/ERK/Brachyury regulatory network by dovitinib and GDC-0973 initiates apoptosis, changes EMT, and inhibits cell growth. The relevance of this proposal: Brachyury is an important hallmark of chordoma. The purpose of this study is to target a novel pathway of FGFR/MEK/ERK/Brachyury to control chordoma cell growth, so positive findings can be translatable to improve outcomes and slow progression of chordoma patients.