New Prospects for Molecular Targets for Chordomas

Abstract

Chordomas are malignant, highly recurrent tumors of the midline skeleton that arise from the remnants of the notochord. The development of systemic therapy is critically important to ultimately managing this tumor. Several ongoing trials are attempting to use molecular targeted therapies for mutated pathways in recurrent and advanced chordomas and have shown promise. In addition, immunotherapies, including brachyury-directed vaccination and checkpoint inhibition, have also been attempted with encouraging results. This article discusses the major pathways that have been implicated in the pathogenesis of chordoma with an emphasis on molecular vulnerabilities that future therapies are attempting to exploit.

Keywords: Brachyury; Chordoma; Immunotherapy; Molecular targeted therapy; Notochord; Receptor tyrosine kinase (RTKs).

Figure 1:. Cellular and epigenetic changes in chordoma and therapeutic opportunities.

A) A schematic of open and closed chromatin and associated epigenetic modulators and transcription factors in normal cells. The panel on the right shows the presence of normal homologous recombination (HR), non-homologous end-joining (NHEJ), cell cycle regulators (CDKN2A, CDKN2B, and CDK4/6), and the H3K36 methyltransferase SETD2 in these cells. B) In chordoma cells, mutations in epigenetic regulators and transcription factors alters the distribution of open and closed chromatin and lead to genome-wide alterations in the epigenetic signature. Together with mutations in the HR, CDKN2A/2B, and SETD2 pathways, this results in uncontrolled proliferation of cells. The drugs shown in panel B) are being used in trials to target the compensatory changes in these pathways in tumor cells to revert the chordoma cells to induce cell senescence or death.

Figure 2:. Molecular pathways targeted in chordomas.

The three major signaling pathways that have been targeted in chordomas. Components of these pathways are frequently mutated in chordomas, resulting in overactivation that results in increased proliferation, upstream of the changes described in Figure 1. Of these pathways, inhibitors to all three receptor tyrosine kinases (RTKs) have been used in clinical trials of advanced or recurrent chordomas, as have RAS/MEK/ERK and PI3K/AKT/PTEN/mTOR inhibitors. JAK/STAT3 inhibitors have shown cell death and reduced proliferation in chordoma cell lines in vitro.