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: Assistant professor Joan Montero, University of Barcelona,
- Second opponent: Professor Therese Standal, NTNU - Norwegian University of Science and Technology,
- Third member and chair of the evaluation committee: Professor Hilde Nilsen, University of Oslo
Chair of the Defence
Assistant professor Tor Erik Rusten, University of Oslo
Principal Supervisor
Researcher Sigrid S. Skånland, Oslo University Hospital
Summary
B-cell malignancies, including chronic lymphocytic leukemia (CLL), exhibit biological and clinical heterogeneity, leading to variable treatment responses. This highlights the need for precision medicine to tailor treatments to individual patients. While genomic precision medicine offers valuable insights, functional precision medicine complements it by directly assessing drug sensitivity and resistance in patient-derived cancer cells.
The aim of this thesis was to develop and apply functional precision medicine approaches for patients with B-cell malignancies, particularly CLL, to improve treatment selection and guide clinical decisions.
We developed an ex vivo co-culture model mimicking the tumor microenvironment (TME), essential for maintaining primary CLL cell viability during functional assays. Engineered fibroblasts expressing TME-relevant ligands (APRIL, BAFF, CD40L) prolonged CLL cell survival and reduced drug sensitivity, confirming the TME’s protective role. Drug screening with this model identified therapeutic options for a relapsed CLL patient.
We also explored the role of PI3K inhibitors in resistant B-cell malignancy models. Drug sensitivity screens revealed that proteasome inhibitors (PIs) were effective in CLL and lymphoma models, including in a patient with refractory CLL. These findings suggest PIs as a promising option for relapsed cases.
Finally, we integrated functional data from drug sensitivity testing, (phospho)protein profiling, and immunophenotyping with genetic and clinical data from 177 CLL patients enrolled in the HOVON141/VISION trial. Using machine learning, we identified predictive biomarkers for progression-free survival with ibrutinib and venetoclax. These functional phenotypes outperformed the CLL-International Prognostic Index.
In conclusion, this thesis demonstrates that functional precision medicine approaches can improve treatment selection and guide clinical decisions for patient with CLL and other B cell malignancies.
Additional information
Contact the research support staff.