Ex vivo drug screening using human tissue to personalise cancer therapy and replace murine avatars

Why did we fund this project?

This award aims to develop a high-throughput ex vivo personalised drug screening method using cells isolated from biopsies of solid tumours, such as glioblastoma, to replace mouse xenograft models.

Targeting treatment specifically to cancer subtypes has been shown to improve patient survival and quality of life. However, due to the large number of mutations present in each tumour identifying which mutations are indicative of susceptibility to a treatment is complex. Typically to analyse treatment options, patient-derived xenograft (PDX) models are generated and drugs administered to the animal to identify those that result in a reduction in tumour size for further investigation. Dr Spencer Collis and colleagues have established an ex vivo screening method where human tumour tissue from a patient biopsy is disaggregated and seeded into multi-well plates, which have been pre-coated with anti-cancer treatments. Using this method, 165 treatment options can be screened using one sample from a patient biopsy.

In this Studentship, the student will improve upon the ex vivo method so that all cell population types present in vivo, including tumour, stem and immunological cells, are maintained increasing clinical relevance and the likelihood of uptake in the research community. In collaboration with Misvik Biology, the student will use confocal immunofluorescence and analysis algorithms to evaluate individualised patient tumour response to treatments. The student will develop skills in cell culture, high-content confocal imaging, immunofluorescence and image analysis.

Personalised medicine represents a departure from traditional ‘one size fits all’ strategies to treat cancer, and extends the concept of stratifying treatment based on the features of a particular tumour to a more intricate, individual level. In recent years, genomic analysis of patient tumours has helped to identify 'actionable' mutations which may suggest susceptibility to a specific therapy. However, relationships between genotype, function and treatment response are often unclear. Increasingly, studies use patient-derived xenograft (PDX) models to provide more direct predictions of drug response for an individual patient. Typically, this involves transplanting tumour tissue from patients into immunocompromised mice. For each patient, tumour from a successfully engrafted mouse would then be expanded in a second cohort of mice, prior to treatment in a third murine cohort. Consequently, even limited studies using these ‘mouse avatars’ may require around 40 mice avatars and many months to provide individualised recommendations from a shortlist of 5 treatment strategies for one patient.

In research, the value of murine avatars generally lies in the opportunity afforded to evaluate hundreds of therapeutic options (rather than a handful) for every human participant. This typically results in heavy animal usage in each study. Our assessment of a sample of research studies which used murine avatars suggests around 300-500+ mice are used per study, and ~15,000-25,000 mice were used globally in this setting over the last 5 years.

This Studentship aims to provide an alternative methodology for solid malignancies which can directly test 165+ treatments using a single, small tumour biopsy from patients without passaging cells. Referred to as ex vivo single-cell drug response profiling – or more simply, ‘ex vivo screening’ – this technique can provide robust and comprehensive personalised treatment recommendations at a fraction of the time and cost incurred by murine avatars. These advantages underline the potential of ex vivo screening to replace the increasing use of murine avatars in personalised medicine and democratise the availability of individualised approaches in research and the clinic.

In collaboration with Misvik Biology – a start-up enterprise with leading expertise in ex vivo screening technology and bespoke analytical software (TrialTest™) – the Studentship will aim to optimise the process of ex vivo screening in tumour samples from patients with glioblastoma (the most common and aggressive brain cancer). Subsequently, ex vivo screening will be used to evaluate over 165 treatment options for 30 consecutive patients, and the predictive value of this methodology will be validated by comparing ex vivo response to current standard treatment (radiotherapy and temozolomide chemotherapy) with survival in the same patients receiving standard treatment. For each patient fresh tumour tissue will be disaggregated into a mixture of cancerous, immune and other normal microenvironmental cell types. These are immediately seeded to multi-well plates which are pre-coated with anti-cancer agents. Multi-parameter, ultrahigh content microscopy and sophisticated image analysis algorithms are used to evaluate treatment response, and rapidly analyse interactions between cancerous cells and tumour microenvironment at single cell resolution, to provide novel biological insights. Professor Helleday et al. anticipate the final optimised protocol for glioblastoma will be easily adaptable to provide screening for other types of solid tumours. Consequently, Professor Helleday et al. believe the studies will demonstrate the feasibility of ex vivo screening as a research tool to generate personalised treatment recommendations for solid cancers more quickly and comprehensively than possible using mouse avatars for drug screening.

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PhD Studentship

Status

Active

Institution

University of Sheffield

Grant reference number

NC/T002093/1

Award date

Oct 2020 - Sep 2023

Grant amount

£90,000