Preclinical Testing of Compounds Identified in a High Throughput Screen as Potential Chordoma Therapies

Chordoma is a rare tumor presumed to be derived from remnants of the notochord.  Conventional chordoma is a low-grade malignancy that can be cured with surgery alone, but because chordomas usually arise in places where resection with negative margins is not feasible, recurrent disease is a problem. There is no effective chemotherapy for recurrent chordoma. Dedifferentiated chordoma is a higher grade malignancy with a moderate metastatic potential. There is no effective systemic therapy for dedifferentiated chordoma, either. Our laboratory (DL) has created the first primary human dedifferentiated chordoma xenograft, and our collaborator (AQ-H) has created a primary chordoma cell line that, whenxenografted in profoundly immune deficient mice recapitulates the histology and behavior of conventional chordoma. Another collaborator (MX) has recently screened approximately 2,800 drugs that have been approved for clinic use or are in clinical trials and identified a series of compounds that appear to have in vitro activity against human chordoma cell lines. We will test candidate compounds, identified in this screen, for in vitro activity against our novel chordoma cell line and for in vivo activity against our conventional chordoma xenograft and against our dedifferentiated chordoma xenograft. The goal of this work is to develop sufficient preclinical data to justify early phase clinical trials for patients with chordoma who require systemic therapy.