Background: Chordoma is a rare cancer found in the base of the skull and the spine that develops from residual embryonic notochord cells. Currently, no systemic therapies are approved for treatment of the disease, but emerging understanding of chordoma biology and tumor dependencies has revealed a number of potential therapeutic targets. To date, validation of novel targets and preclinical evaluation of corresponding therapies has been hampered by scarcity of preclinical models as well the high cost of starting in-vivo experiments. To facilitate more rapid and efficient evaluation of new therapeutic approaches, the Chordoma Foundation has developed a centralized Drug Screening Program (DSP) operated through a partnership with South Texas Accelerated Research Therapeutics (START).

Methods: Patients undergoing surgical resection are consented through the Chordoma Foundation's IRB approved biobanking protocol. Tumor tissue is shipped to START, engrafted in immunodeficient mice, and expanded. Resulting patient-derived xenograft (PDX) models are validated by confirmation of histology and expression of brachyury, a protein highly expressed in chordoma tumors. Additional PDX models and cell line derived xenograft (CDX) models are acquired from academic institutions and established at START for use in screening experiments. Drugs are nominated by academic and industry investigators and prioritized by the Chordoma Foundation on the basis of molecular rationale and existing in vitro data. Selected drugs are evaluated for efficacy in the panel of PDX and CDX models. Data is provided back to the nominating investigator, and, when permitted, is made public through an online data repository.

Results: A diverse collection of seven validated PDX and CDX models has been developed and is available for in-vivo drug screening experiments. These models represent different clinical subtypes of chordoma, including five derived from conventional chordomas and two derived from poorly differentiated tumors, the latter being an aggressive subtype of chordoma typically found in pediatric patients and young adults. To date, twenty-four drugs have been tested as single agents or in combination in various models. A range of activities have been observed, which may be dependent on molecular alterations present in the individual models. Inhibitors of EGFR and CDK4/6 demonstrated the greatest activity across models. This data has supported the initiation of two clinical trials specific for chordoma patients testing the targeted agents afatinib and palbociclib.

Conclusion: The Chordoma Foundation's DSP serves as a core facility for the chordoma research community, providing investigators with a rapid and low-cost means of evaluating novel targets and therapies. It overcomes a key barrier to chordoma drug development and may provide a template that can be employed to other cancer types.

Citation Format: Patricia Cogswell, Michael Wick, Melissa Rundle, Amanda Mangold, Josh Sommer, Joan Levy. Rapid and efficient evaluation of drug sensitivity in a diverse panel of chordoma xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2150.