Drug repurposing for oesophageal cancer

Using imaging microscopy and phenotypic screening to identify drug repurposing and potential new drug discovery

Oesophageal Cancer is the seventh most common cancer type and sixth most common cause of cancer mortality worldwide. This is a complex heterogeneous disease characterized by large scale genomic rearrangements and no common oncogenic drivers, confounding modern target-based drug discovery strategies. As a consequence prognosis is poor and 5-year survival rates are < 20%, global incidence has been increasing steadily over several decades, thus oesophageal cancer represents a major global health problem.

Using automated high content imaging microscopy we conducted a high throughput screen of 20,000 small molecule compounds across six human oesophageal cancer cell lines representing the broad genetic heterogeneity of disease and two non-transformed tissue matched control cell lines. Using a “Cell Painting” assay and bespoke image analysis algorithm we extracted 720 features per cell in every image to obtain a multiparametric phenotypic fingerprint for every cell following compound treatment. Phenotypic fingerprints were interrogated by multivariate statistics and machine learning models to classify cell phenotype and drug mechanism-of-action. This high content screening data set is comprised of 3.9million images (30Tb data). This single phenotypic screen identified several drug repurposing opportunities, potential new therapeutic targets and 4 attractive chemical starting points for novel drug discovery programs targeting oesophageal cancer.

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