Recent advances in bladder cancer research have identified and defined subtypes of bladder cancer based on the presence of specific molecular markers. In light of this discovery, it has become apparent that current disease models do not represent the full range of bladder cancer subtypes. Cells can be isolated from patient tumour tissue and used to generate patient-derived xenograft (PDX) models in immunocompromised mice. PDX mice can then be used to provide a comprehensive overview of the sensitivity of the tumour and the tumour microenvironment to cancer therapeutics. However, the available tumour cell lines and the majority of PDX models are biased towards more aggressive tumour subtypes. As such, new models are required for both functional investigations and preclinical drug assessments.
Why we funded it
This studentship aims to replace the need for PDX mice in the study of bladder cancer with the development of a bank of in vitro models which represent the full range of bladder cancer subtypes defined.
297 publications using PDX mice in urinary bladder studies have been published, with 112 of these published since 2014. These publications typically required a total of ~60 animals per study, with 4-7 animals used per condition, resulting in ~3,360 animals needed per annum. Professor Knowles and colleagues estimate 75% of such experiments could be replaced with the organoids developed in this studentship. These estimations exclude animal use in industry.
Human cells derived from tumours, or normal tissues, can be maintained in in vitro 3D organoids and banks of organoids have previously been established for colorectal and prostate cancers. This studentship aims to develop culture conditions suitable for long-term in vitro organoid culture of patient-derived bladder cancer tissues, and create a bank of organoids representing the full range of molecular subtypes now known to exist. Cancer subtypes show variable sensitivity to therapeutics but PDX models are not suitable for rapid drug sensitivity assessment for individual patients. After the bank of organoids has been established they will be used in combination with a novel microfluidics platform for drug sensitivity studies. Initial experiments will look to demonstrate comparability to pre-existing PDX models before the organoids are used for rapid evaluation of patient samples in drug sensitivity studies.