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

Doktorsavhandling
Författare Berglind Einarsdottir
Datum för examination 2017-05-26
Opponent at public defense Richard Marais
ISBN 978-91-629-0162-2
Förlag University of Gothenburg
Förlagsort Gothenburg
Publiceringsår 2017
Publicerad vid Institutionen för kliniska vetenskaper, sektionen för kirurgi och kirurgisk gastroforskning, Avdelningen för kirurgi
Språk en
Länkar hdl.handle.net/2077/51878
Ämnesord malignant melanoma, patient-derived xenografts, MTH1, pre-clinical trial, Karonudib
Ämneskategorier Cancer och onkologi, Cellbiologi, Medicinsk cellbiologi

Sammanfattning

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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