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Program Number: B260
Session Name: Poster Session

High throughput drug screening on head and neck cancer organoids reveals novel therapeutic strategies

Matthew Spence, BA¹; Isabel R Cioffi, BS²; Yasuto Tomita, MD²; Samuel P Flashner, PhD³; William R Britton, BS¹; Cecilia Martin, MS⁴; Lingyi Cai, MS⁵; Luqman K Dad, MD, MBA⁶; Brian S Henick, MD⁷; Salvatore M Caruana, MD⁸; Scott H Troob, MD⁸; Dimitris Anastassiou, MS, PhD⁹; Hiroshi Nakagawa, MD, PhD¹⁰; Anuraag S Parikh, MD⁸; ¹Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; ²Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; ³Herbert Irving Comprehensive Cancer Center and Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY; ⁴Herbert Irving Comprehensive Cancer Center and Organoid and Cell Culture Core, Digestive and Liver Diseases Research Center, Columbia University, New York, NY; ⁵Department of Systems Biology and Department of Electrical Engineering, Columbia University, New York, NY; ⁶Department of Radiation Oncology, Columbia University, New York, NY; ⁷Herbert Irving Comprehensive Cancer Center and Columbia Center for Translational Immunology Columbia University, New York, NY; ⁸Department of Otolaryngology-Head and Neck Surgery, Columbia University, New York, NY; ⁹Herbert Irving Comprehensive Cancer Center and Department of Systems Biology and Department of Electrical Engineering, Columbia University, New York, NY; ¹⁰Herbert Irving Comprehensive Cancer Center and Division of Digestive and Liver Diseases and Organoid and Cell Culture Core, Columbia University, New York, NY

Introduction: Head and neck squamous cell carcinoma (HNSCC) remains the seventh most common form of cancer worldwide. Although the genetics and epigenetics of head and neck tumors have been better understood over the past decade, targeted therapies are still quite limited, with standard treatments including surgery, radiation, and chemotherapies. One challenge to the growing field of precision medicine is that in vitro experiments on traditional 2D cell lines do not readily translate to the clinical setting. This study utilizes a high-throughput drug screen in 3D patient-derived organoids (PDOs) to better capture inter- and intra-tumoral heterogeneity, which are known to be key contributors to poor outcomes in HNSCC.

Methods: PDOs were generated from two normal, one dysplastic, and five HNSCC tissue samples, according to our previously established protocols. A high-throughput drug screen was conducted using a single dose (10 μM) of 433 biologically and pharmacologically significant compounds from 13 different and broad drug classes across these eight PDOs. Meticulous optimization of cell seeding and drug application was undertaken to facilitate these experiments in a 384-well plate format. 300 cells per well were initially seeded and organoids were allowed to develop for 7 days. Drugs were added on day 7 and cell viability was measured on day 11 using the CellTiter-Glo luminescence assay. Dimethyl sulfoxide and thimerosol were used as negative and positive control, respectively.

Results: Consistent with the variability in patient response to standard treatments, the PDOs demonstrated heterogeneity in responsiveness to the compounds. Of the 433 compounds, 96 drugs (22.1%) were effective against 4-6 of the dysplastic and cancerous organoid lines. Of these, 4 exhibited ≥ 50% selectivity for tumor tissue compared to normal (pracinostat, tanespimycin, SB-743921, and mocetinostat). Drugs in the protein class (n=32), including heat shock protein 90 (HSP90), proteasome, and protein synthesis inhibitors, as well as epigenetic modifying drugs (n=15) had the highest proportion of hits for ≥ 4 of the dysplastic and HNSCC PDOs (75% and 53%, respectively). Further analyses investigating specific targets within each drug class showed HSP90 and histone deacetylase (HDAC) inhibitors to have the most hits within their respective class. Overall, the HNSCC PDOs demonstrated a more drug-resistant profile than both the dysplastic and normal organoids. Dose response experiments and broader testing across a larger organoid cohort are ongoing.

Conclusions: High-throughput drug screening across eight normal, dysplastic, and HNSCC PDOs revealed protein and epigenetic targeting drugs to have the most proportional hits. Specifically, HSP90 and HDAC inhibitors were most effective within their drug class. Pending dose response experiments and validation across a larger cohort, these results provide potential novel protein and epigenetic targeting strategies as promising approaches in HNSCC.

 

 

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