Bokea, Kalliopi; (2025) Establishment of Patient-Derived 3D Tumouroids and Matched Xenografts: Personalised Medicine Tools for Renal Cancer. Doctoral thesis (Ph.D), UCL (University College London).

Text PhD Thesis Kalliopi Bokea.pdf - Accepted Version Access restricted to UCL open access staff until 1 March 2026. Download (8MB)

Abstract

Despite the therapeutic advancements in the management of Renal Cell Carcinoma (RCC), there is an unmet clinical need for patient-specific in vitro models that can predict patients’ response to therapy and replace the dependence on animal models. Here, biomimetic 3D in vitro RCC models, termed tumouroids, were established, incorporating patient-derived tumour cells and a complex stroma to mimic the physiological tumour microenvironment. Tumouroids of different complexity were manufactured: simple tumouroids consisting of patient-derived tumour cells and complex tumouroids incorporating an additional stromal compartment populated with fibroblasts and endothelial cells. Resemblance to the original tissue was investigated and response to a tyrosine kinase inhibitor (TKI) used in the treatment of advanced RCC, Pazopanib (Votrient™), was compared among different culture conditions and levels of in vitro model complexity. Cell line xenografts were developed to investigate the in vivo signature of response to Pazopanib. Finally, matched tumouroids and xenografts were established from one patient, to compare the two models in terms of resemblance to original tissue, response to pazopanib and genetic profile. 3D tumouroids were successfully established from RCC patient samples (n=21) and mimicked the phenotype of the original tumour, retaining the expression of characteristic RCC markers, as well as the subtype-specific histology of the original tumour. Treatment with Pazopanib revealed a range of responses, ranging from none to strong, for individual patient-derived simple tumouroids. The tumour microenvironment was successfully mimicked in the complex tumouroids, where stronger responses were observed due to the disruption of the endothelial networks in addition to the direct killing of the tumour cells. Similarly, tumour size and vessel density were reduced in vivo after pazopanib treatment of cell line xenografts. Matched patient-derived tumouroids and xenografts mimicked the original tumour and responded similarly to pazopanib. Genetic analysis revealed that both models preserved the genetic profile of the original tumour. However, for patient-derived xenografts lower engraftment and establishment success rates were reported, with increased variability in tumour progression among individual mice and longer and more challenging protocols. In conclusion, patient-derived tumouroids mimicked the original tissue, distinguished between different drug responses and successfully reproduced the signatures of response to TKIs as seen in vivo. In addition, their feasibility to establish compared to patient-derived xenografts, supports their suitability as personalised cancer treatment platforms.

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