Abstract
Background
Bladder cancer (BC) is the tenth most common cancer and the ninth leading cause of cancer death worldwide. BC has high rates of treatment failure, so alternate approaches are needed to personalise treatments to individual patients in order to improve outcomes from this disease. One method that could provide actionable results to influence clinical decisions on alternative treatments is ex vivo drug screening.
Methods
We explored the feasibility of using ex vivo drug screening directly on patient tumour tissue from transurethral resection of the bladder tumours (TURBT) and cystectomies. We screened 38 BC patients investigating drug sensitivities to 15 agents, including standard of care treatments and some more exploratory compounds. In addition, we investigated ex vivo sensitivity and resistance over the 15 compounds and annotated common mutational profiles. We saw high methodological success (41/54 samples, 75.9%), in clinically useful timeframes (4 days) and identified distinct drug and tumour clusters.
Results
Here, we show that drug resistance is associated with aggressive clinical features, mutation burden, and differs with individual gene mutations. Cross-resistance between agents is common. Cisplatin-resistant tumours differ by mutational profiles and include those with multi-drug resistance and those sensitive to alternative agents. Observed clinical responses match our ex vivo response (5/6 patients, 83.3%). Proliferative responses are observed to some receptor tyrosine kinase inhibitors, cautioning against their unselected widespread use.
Conclusions
Ex vivo drug screening identifies drug clusters of patients’ tumours that could potentially respond to standard of care and alternative therapies. Our approach offers a platform to potentially individualise treatments, especially in drug-resistant tumours.
Plain language summary
Bladder cancer is the ninth leading cause of cancer death worldwide and has high rates of treatment failure. Therefore, alternative approaches are needed to personalise treatments to individual patients to improve outcomes. In this study, we investigate the feasibility of using cancer drugs directly on patient tumour cells removed from the body to identify which drugs may or may not work. To test this, we investigated 15 cancer treatments on 38 patient tumour samples. We investigated both established drugs and cutting-edge treatments. We found that drug resistance was higher in patients with aggressive cancers and that 5 out of 6 patients showed the same response to drug treatment as their tumour cells did outside their body. We identify different subtypes of bladder cancer patients who could respond to different medicines. Screening drugs outside of the body has shown that it can be used to identify effective medicines prior to the patient undergoing treatment and identify different treatments. This could be used in the future to identify the best cancer medicine specific to the patient.
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Acknowledgements
We first and foremost would like to acknowledge the participants for their engagement in this study and for donating their tissue. We gratefully acknowledge the support of investigators, research nurses, and other site staff who have supported the study. We would like to thank The Urology Foundation, who have provided ongoing support for this project and to SC throughout her academic career progression. SC would also like to acknowledge the Royal College of Surgeons of England for supporting this project through their One Year Surgical Research Fellowship. JWFC is funded by an NIHR Research Professorship. The University of Sheffield Knowledge Exchange and Weston Park Cancer Centre funded all consumables. STW was supported by the NIHR and continues to be supported by a Wellcome Trust PhD Fellowship. JG is funded by an NIHR Clinical Lectureship and a Clinical Lecturer Support Grant from The Pathological Society of Great Britain and Ireland. The funders had no role in the design, analysis or collection of the data; in writing the manuscript; or in the decision to submit the manuscript for publication. We are grateful for the study oversight provided by the sponsor, Sheffield Teaching Hospitals NHS Foundation Trust. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. University of Sheffield Institutional Open Access Fund.
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S.C. has received speaker fees from InMed. S.A.H has received research funding from Cancer Research UK, MRC/NIHR, UHB charities, CCC charities, North-West Cancer Research, Yorkshire Cancer Research, Weston Park Cancer Charity, Bayer, Janssen, Boehringer Ingelheim, Pierre Fabre, Eli Lilly, Roche, and has received advisory board/consultancy fees from Roche, MSD, AstraZeneca, BMS, Janssen, GSK, Astellas, Pfizer, Bayer, Merck, Pierre Fabre, Sotio, Gilead. JG has received research funding from Roche and in-kind research support from Owkin and has received honoraria from ISSECAM. JKR is the founder of Misvik Biology Ltd and has received research funding from AstraZeneca and Boehringer Ingelheim. SJD has received consulting fees from Orion Therapeutics, Oxcia and Incanthera. JWFC has received consulting fees from AstraZeneca, Ferring, Ipsen, Roche, and Janssen; has received speaker fees from Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Janssen, Astellas, Nucleix, InMed, and Roche; has received honoraria for membership in advisory boards from Ferring, Roche, Gilead, Photocure, Pfizer, Bristol Myers Squibb, QED Therapeutics, and Janssen; and has received research funding from Roche. HG, LAQ, STW, TH, RA, and GW have declared no conflicts of interest.
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Conroy, S., Gagg, H., Quayle, L. et al. Ex vivo drug screening and clustering of bladder cancers for pre-clinical treatment prediction. Commun Med (2026). https://doi.org/10.1038/s43856-026-01596-5
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DOI: https://doi.org/10.1038/s43856-026-01596-5
