Abstract 2126: Development of a precision chordoma research program

Abstract

Abstract Chordomas are malignant tumors of the axial skeleton that originate from remnants of the embryonic notochord. With an incidence of one per million per year, chordoma is a rare disease that accounts for 1-4% of all bone tumors and approximately 20% of primary spinal tumors. As first-line treatment, patients undergo surgical resection followed by adjuvant radiotherapy, whereas most chordomas are resistant to conventional cytotoxic drugs and there are no clinically validated molecular drug targets. To overcome the lack of effective medical treatment and to better understand chordoma biology, we have established a chordoma precision research program. Here, whole-exome or genome and transcriptome sequencing are used to determine mutational landscapes, DNA copy number profiles, and transcriptome changes in chordoma cell lines and patient samples. Additionally, large-scale functional genomic screens and (phospho-)proteomic analyses have been performed in multiple chordoma cell lines to identify new chordoma-specific vulnerabilities. Based on these multilayered datasets, we selected a panel of previously unrecognized candidate chordoma driver genes, which are currently being validated as novel therapeutic targets using genetic and pharmacologic approaches. In addition to this unbiased approach, we seek to inhibit the embryonic transcription factor brachyury, an established driver of chordomagenesis. Although brachyury represents, in principle, a promising therapeutic target, inhibition of transcription factors remains difficult. To circumvent this challenge, we are developing Designed Ankyrin Repeat Proteins (DARPins) that specifically prevent the binding of brachyury to DNA. These DARPins are not only a valuable tool for studying chordomagenesis, but also represent a new class of molecularly targeted agents that might be used for the treatment of chordoma patients. In summary, using multi-omics data, functional genetics, and inhibition of an established chordoma driver, we are working towards a better understanding of chordoma biology and the development of new therapeutic approaches. Updated results of the precision chordoma research program will be presented. Citation Format: Marie Groth, Jana Kress, Matea Hajnic, Joana Marinho, Kevin Mellert, Thomas F. Barth, Peter Möller, Birgit Dreier, Andreas Plückthun, Claudia Scholl, Stefan Fröhling. Development of a precision chordoma research program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2126.