Abstract 3914: High-throughput drug screening of personalized chordoma organoids: A case series of six patients
Authors: Davarifar Ardy , Nguyen Huyen T. , Tavanaie Nasrin , Yanagawa Jane , Damoiseaux Robert , Federman Noah , Bernthal Nicholas , Nelson Scott , Hornicek Francis , Soragni Alice 
Published: September 2020

Abstract
Chordoma is a rare malignant tumor that arises from embryonic remnants of the notochord (Sahyouni et al, J Neurosurg Spine, 2018). This tumor is highly chemotherapy resistant, and there are no known compounds which have demonstrated clinically significant remissions (Gelderblom et al, Oncologist, 2008). With local therapies (surgery and/or radiation), local recurrence rates are high (∼40%). Repeated surgeries with or without radiation have dismal results (Fuch et al, J Bone Joint Surg, 2005). Systemic therapies are largely ineffective and often highly toxic.
Given its rarity, there is limited randomized clinical data regarding effective treatments. Moreover, less than ten validated chordoma cell lines and fewer PDX models are currently available, further hindering drug development and discovery studies (Bosotti et al, Sci Reports, 2017).
Here, we take advantage of tumor organoids to establish chordoma models that can be rapidly and effectively screened ex vivo to identify effective therapies. Tumor organoids are capable of reproducing many crucial features of the cancer they are generated from, including heterogeneity, cell organization as well as drug response. We have developed an automated high-throughput screening platform to test the response of patient-derived tumor organoids to hundreds of therapeutic agents, with results available within a week from surgery, a timeline compatible with therapeutic decision-making (Phan et al, Communications Biol, 2019). Here we show how our platform can be effectively used to investigate drug susceptibilities and heterogeneity in chordoma.
Fresh tumour tissue from n=6 patients obtained from needle biopsies or surgical resections was processed to single cell suspension prior to establishing organoids according to our unique geometry. We performed a drug screening of up to 230 compounds on seven samples established from n=6 patients and determined organoid viability after a 48h exposure to the drugs. Our data suggest the potential efficacy of particular compounds that target the mTOR and PI3K pathways. We will show validation as well as histopathology of the organoids including staining for S100, Ki-67 and brachyury that was observed also in the pathology of specimens derived from the same patient.
Overall, we have successfully established organoids from chordoma patients with a 100% success rate and 7/7 specimens growing and yielding biologically and therapeutically relevant models. Our methodology allows us to perform large drug screenings including for low grade chordomas, which are typically refractory to growth in immunocompromised mice as patient-derived xenografts.
Determining the clinical efficacy of any new therapeutic approach is challenging in chordoma due to its natural history and slow growth rates. Our organoid-based functional sensitivity profile may be used to tailor therapy to each patient and to potentially rule out ineffective drugs, thus sparing ineffective therapies and associated toxicities.
Citation Format: Ardy Davarifar, Huyen T. Nguyen, Nasrin Tavanaie, Jane Yanagawa, Robert Damoiseaux, Noah Federman, Nicholas Bernthal, Scott Nelson, Francis Hornicek, Alice Soragni. High-throughput drug screening of personalized chordoma organoids: A case series of six patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3914.