Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Adjunct Professor Jeroen Pouwels, Neurotar Oy Ltd, Finland
- Second opponent: Professor Ole Morten Seternes, UiT - Arctic University of Norway, Norway
- Third member and chair of the evaluation committee: Associate Professor June Helen Myklebust, Faculty of Medicine, University of Oslo
Chair of the Defence
Professor emerita Torill Sauer, University of Oslo
Principal Supervisor
Professor II Kristine Kleivi Sahlberg, Department of Research and Innovation, Vestre Viken Hospital Trust; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo
Summary
HER2-positive breast cancer is an aggressive disease that historically was associated with poor outcome. Over the past decades, the prospects for patients with HER2-positive breast cancer have improved due to therapy that directly targets cells overexpressing the tyrosine kinase receptor HER2 (human epidermal growth factor receptor 2). However, some patients do not respond to treatment and need new alternatives. In this thesis, Lisa Svartdal Normann and colleagues have studied new drug combinations pre-clinically to address this.
The main aim of the study has been to identify therapeutic compounds that can sensitize cancer cells to the targeted drugs trastuzumab and lapatinib. Two high-throughput screens were performed using HER2-positive breast cancer cells that respond poorly to targeted therapy. One screen included >270 drugs, and the other screen contained >1600 microRNAs. The endpoint of the screens was to measure viability and protein expression.
The drug screen identified the Src-inhibitor dasatinib as a candidate to reduce cell viability in combination with lapatinib. However, the promising results in vitro were not recapitulated in vivo. Protein expression data from PDX models suggested increased levels of insulin receptor and phosphorylated HER2, which may contribute to the lack of effect in the combination treatment vs control.
The microRNA screen identified miR-101-5p as an agent with promising potential alone and with lapatinib in preventing cell viability in vitro, making it an interesting candidate for further work. Protein expression data from treated cells suggested an effect on signaling pathways such as PI3K-Akt, and initiation of apoptosis. Further, a higher expression level of miR-101-5p in patients was associated with improved breast cancer specific and overall survival.
In short, Normann and colleagues have identified several microRNAs and drugs that inhibited cancer cell viability alone and in combination with lapatinib and/or trastuzumab.
Additional information
Contact the research support staff.