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Development and application of a patient-derived xenograft platform to test anticancer agents

Doctoral thesis
Authors Berglind Einarsdottir
Date of public defense 2017-05-26
Opponent at public defense Richard Marais
ISBN 978-91-629-0162-2
Publisher University of Gothenburg
Place of publication Gothenburg
Publication year 2017
Published at Institute of Clinical Sciences, Department of Surgery
Language en
Links hdl.handle.net/2077/51878
Keywords malignant melanoma, patient-derived xenografts, MTH1, pre-clinical trial, Karonudib
Subject categories Cancer and Oncology, Cell Biology, Medical cell biology

Abstract

Malignant melanoma is the most aggressive form of skin cancer and incidence rates are on the rise. Despite recent improvements in treatment options, the disease still remains lethal. Which calls for expedited solutions. In this thesis I will discuss three studies, which have not only contributed new knowledge to the research community but also led to development of tools used in cancer research. In the first paper we developed a platform of patient-derived xenografts (PDXes) from metastatic melanoma patients. We show that PDXes can accurately predict clinical treatment responses and that the xenografts can be established in time to benefit the patients. Thus, the platform can be used for multiple pre-clinical and clinical purposes. In the second paper we compared the transcriptome of cell line-derived xenografts (CDXes) and PDXes. The initial aim was to investigate if CDXes would be transcriptionally similar to PDXes and could therefore be used as in vitro surrogates for the PDXes. Instead, we identified a significant transcriptional difference between CDXes and PDXes, mainly explained by the pseudo hypoxia experienced by the cell lines once they are transplanted to the physiological environment. In the third paper, we ran a pre-clinical trial in malignant melanoma PDX mouse models with the aim of identifying a predictive biomarker of the MTH1 inhibitor, Karonudib. By comparing the genomic and transcriptomic profiles of the responding and non-responding PDXes we identified that Karonudib has cytotoxic effect independent of those profiles. Also, we discovered that Karonudib causes cytotoxic effect beyond MTH1 inhibition. Taken together, our data shows that PDX models predict clinical responses and can be used to test drugs pre-clinically, and argues that pre-clinical testing in PDX models is superior to cell line based drug testing.

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