Large scale expansion of patient-derived breast cancer organoids to transform drug discovery screening assays


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Mairian Thomas1,Andrew Hollins2,Trevor Dale2,Marianne Ellis1
1Cellesce Ltd,2Cardiff University

Abstract

Background

Organoid technology has the potential to transform drug discovery, by providing better predictive efficacy and toxicity assays than current 2D models and reducing the requirement for animal models in the drug discovery pipeline. However, the production of organoids at scale, for use in medium-to-high throughput assays, is currently a bottleneck: highly time consuming and labour intensive, with batch-to-batch variation limiting assay reproducibility.

Cellesce are currently developing bioprocessing systems for the expansion of organoids in significant volumes in a way that minimises handling time and maximises reproducibility, with the long-term goal of positioning organoid technology as a cost-effective model for early-stage drug discovery.

Method

Following the successful expansion and commercialisation of 10 human colorectal cancer organoid lines using proprietary bioreactor technology, Cellesce is now broadening its product range to include other tissue types. In collaboration with Cardiff University, Cellesce has begun optimisation of the bioreactor system for the expansion of patient-derived breast tumour organoids.

Results

In this proof-of-principle study, Cellesce has assessed the stability of breast cancer organoid morphologies, HER2 and hormone receptor expression, along with other histopathologic markers following large-scale bioreactor expansions. Whole exome sequencing, RNAseq and qRT-PCR data have also been used to assess the retention of the genotype and gene expression initially observed in manually expanded organoids.

 

Comparison of breast organoids grown manually and those grown using bioreactor technology shows that bioreactor expanded organoids do maintain functional drug responses. Moreover, expanded organoids demonstrate reduced well-to-well variability and greater batch-to-batch reproducibility than their manually grown counterparts in drug response assays, thus reinforcing their potential utility in high throughput drug screening.

 

Conclusion

Cellesce will use the results of this study to direct the further expansion of breast cancer organoids in sufficient quantities to produce frozen batches that can be provided for sale for use ‘off the shelf’.