High-Throughput Drug Screening of FDA-Approved Cancer Drugs Reveals Novel Therapies for Patients with Chordomas

Background: Chordomas are a rare tumor of the central nervous system that originate from the notochord. These tumors have a 5-year recurrence rate of ~45%. Aside from surgery and radiation, no other therapies are available for the treatment of these tumors. This is in part due to a lack of cell lines to use for drug screening and a small patient population for the implementation of clinical trials. In recent years, the Chordoma Foundation started an initiative to incentivize researchers to generate chordoma cell lines. This has led to the establishment of 16 chordoma cell lines to date, 11 of which were generously donated to our institution. With these cell lines, we now have the ability to screen these cells for drug sensitivity to identify novel therapeutic targets and to identify potential FDA approved drugs for the immediate treatment of chordomas. Our work has the potential to rapidly accelerate the rate of therapy discovery for the treatment of patients with a chordoma.

Methods: We have adapted our high-throughput assay developed for meningiomas to accommodate the screening of chordomas. These cell culture modifications have also allowed us to expand cells from patient tumors. In this study we screened the National Cancer Institute’s 129 compound FDA approved cancer therapy drug panel against our cohort of established chordoma cell lines and cells expanded from patient derived tumors. The screen was performed at a single concentration of 1um. Any compound that resulted in a loss of cell viability of 50% or more at this concentration was considered a positive hit.

Results: A small cohort of compounds were identified with the ability to inhibit chordoma growth, and included compounds from classes that inhibit DNA synthesis, RNA synthesis, SRC related signaling pathways, and tyrosine kinase receptors. Two of these compounds, ponatinib and brigatinib, inhibit several of these pathways. Ponatinib inhibits a broad spectrum of tyrosine kinase receptors including ABL, PDGFR, VEGFR, and FGFR, in addition to inhibiting SRC family kinases. Brigatinib has a similar spectrum of inhibition which includes the tyrosine kinase receptors ABL, IGF1R, INSR, and EGFR, as well as the FES/FER kinases, FLT3, and ROS1. These findings are consistent with one of our previous publications that showed FES/FER and SRC signaling was highly upregulated in recurrent chordomas.

Conclusion: We have performed a high-throughput drug screen in chordoma cell lines to look for sensitivity to FDA approved cancer therapeutics. Given that all of these compounds are FDA approved, positive hits can be used for the immediate treatment of chordomas. Ponatinib and brigatinib are two such compounds whose targets have been implicated in previous research to drive chordoma recurrence, and thus have a high potential to efficaciously treat patients suffering from chordomas.